The Molecular Basis of Human Retinal and Vitreoretinal Diseases

Berger, W; Kloeckener-Gruissem, B; Neidhardt, J (2010). The molecular basis of human retinal and vitreoretinal diseases. Progress in Retinal and Eye Research, 29(5):335-375. Postprint available at: http://www.zora.uzh.ch University of Zurich Posted at the Zurich Open Repository and Archive, University of Zurich. Zurich Open Repository and Archive http://www.zora.uzh.ch Originally published at: Progress in Retinal and Eye Research 2010, 29(5):335-375.

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The molecular basis of human retinal and vitreoretinal diseases

Berger, W; Kloeckener-Gruissem, B; Neidhardt, J

Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch

Originally published at: Progress in Retinal and Eye Research 2010, 29(5):335-375. The molecular basis of human retinal and vitreoretinal diseases

The molecular basis of human retinal and vitreoretinal diseases

Wolfgang Berger1,2,3,*, Barbara Kloeckener-Gruissem1,4 and John Neidhardt1

1Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland

2Neuroscience Center Zurich, Zurich, Switzerland

3Zurich Center for Integrative Human Physiology, Zurich, Switzerland

4Department of Biology, ETH Zurich, Zurich, Switzerland

*Corresponding author

Address:

Division of Medical Molecular Genetics and Gene Diagnostics Institute of Medical Genetics University of Zurich Schorenstrasse 16 CH-8603 Schwerzenbach Switzerland

Tel.: + 41 44 655 70 31 Fax: + 41 44 655 72 13 Email: [email protected] http://www.medmolgen.uzh.ch

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

1. Introduction

2. Non-syndromic retinal and vitreoretinal diseases

2.1 Diseases of rod photoreceptor cells (stationary and progressive) 2.1.1 Stationary rod diseases / Congenital stationary night blindness (CSNB) 2.1.2 Retinitis pigmentosa (RP) / Progressive rod diseases

2.2 Cone and cone rod diseases (stationary and progressive) 2.2.1 Stationary cone dysfunctions / Color vision defects (CVD) 2.2.2 Cone and cone rod dystrophies (CODs and CORDs) 2.2.3 Macular degenerations (monogenic and age-related)

2.3 Generalized photoreceptor diseases 2.3.1 Leber congenital amaurosis (LCA) 2.3.2 Choroideremia 2.3.3 Gyrate atrophy of the choroid and retina

2.4 Vitreoretinopathies 2.4.1 Erosive vitreoretinopathies (ERVR) 2.4.2 Exudative vitreoretinopathies (EVR)

3. Syndromic retinal and vitreoretinal diseases

3.1 Usher syndrome (USH) 3.2 Bardet Biedl syndrome (BBS) 3.3 Senior Loken syndrome (SLSN, NPHP) 3.4 Refsum syndrome (Batten disease) 3.5 Joubert syndrome (JBTS) 3.6 Alagille syndrome (ALGS) 3.7 Alström syndrome (ALMS) 3.8 Neuronal ceroid lipofuscinosis (NCL, CLN) 3.9 Primary ciliary dyskinesias (PCD) 3.10 Stickler syndrome (STL)

4. Genetic testing and counselling

5. Therapeutic approaches to retinal degenerations

6. Conclusions and outlook

7. References and Internet Resources

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

Abstract

During the last two to three decades, a large body of work has revealed the molecular basis of many human disorders, including retinal and vitreoretinal degenerations and dysfunctions. Although belonging to the group of orphan diseases, they affect probably more than two million people worldwide. Most excitingly, treatment of a particular form of congenital retinal degeneration is now possible. A major advantage for treatment is the unique structure and accessibility of the eye and its different components, including the vitreous and retina. Knowledge of the many different eye diseases affecting retinal structure and function (night and color blindness, retinitis pigmentosa, cone and cone rod dystrophies, photoreceptor dysfunctions, as well as vitreoretinal traits) is critical for future therapeutic development. We have attempted to present a comprehensive picture of these disorders, including clinical, genetic and molecular information. The structural organization of the review leads the reader through non-syndromic and syndromic forms of (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal degenerations and (iv) vitreoretinal disorders, caused by mutations in more than 165 genes. Clinical variability and genetic heterogeneity have an important impact on genetic testing and counselling of affected families. As phenotypes do not always correlate with the respective genotypes, it is of utmost importance that clinicians, geneticists, counsellors, diagnostic laboratories and basic researchers understand the relationships between phenotypic manifestations and specific genes, as well as mutations and pathophysiologic mechanisms. We discuss future perspectives.

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

1. Introduction

Monogenic diseases of the retina and vitreous affect approximately 1 in 2000 individuals, or more than 2 million people worldwide. Consequences for affected individuals are variable and can range from legal blindness in the most severe forms of retinal degenerations (Leber congenital amaurosis, LCA) to less severe or rather mild retinal dysfunctions (night blindness, achromatopsia). For most of them, no treatment can be offered. In the past 20-25 years, the knowledge about the molecular basis of retinal diseases has tremendously progressed and evidence for the contribution of genetic factors but also environmental circumstances is continuously accumulating. After a time period that was mainly characterized by the identification of genes and disease causing mutations for the monogenic retinal and vitreoretinal traits in families, we have now entered an era where not only monogenetic (classic

Mendelian) but also multifactorial diseases are in the interest of clinical, genetic and basic research. Still, a reliable molecular diagnosis is possible for only half of the affected individuals or families with monogenic forms of retinal diseases. In addition, the predictive value of a mutation or risk allele for multifactorial disorders is problematic since the phenotypic and/or symptomatic consequences are highly variable. Nevertheless, the knowledge about the molecular mechanisms has also improved diagnostic assessment of patients by genetic testing. It is the ultimate goal to better understand the molecular etiology of these diseases and to develop approaches for therapeutic interventions.

The diseases discussed in this article can be categorized in four major groups: (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal degenerations (affecting both photoreceptor cell types, rods and cones), and finally

(iv) exudative as well as erosive vitreoretinopathies (Figure 1). Our disease classification also considers whether the ocular phenotype is associated with

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

pathologies of other tissues (syndromic forms) or only affects the retina, retinal pigment epithelium and the vireous body (non-syndromic forms). In addition, the mode of inheritance was used as one characteristic feature of the different disease phenotypes in order to categorize them. Our aim was to provide a comprehensive overview about the molecular basis of retinal and vitreoretinal diseases and to discuss selected aspects in more detail.

2. Non-syndromic retinal and vitreoretinal diseases

2.1 Diseases of rod photoreceptor cells (stationary and progressive)

Rod photoreceptors represent the vast majority of light sensitive cells in the human retina. There are approximately 20 times more rods than cones. These cells are spezialized for low light intensities and are responsible for visual perception under dim light conditions. The center of the human retina, which contains the macula and fovea centralis, is devoid of rod photoreceptor cells but the flanking areas have the highest rod content, which decreases almost lineary towards the retinal periphery.

The two major classes of stationary and progressive retinal diseases in humans are represented by different forms of stationary night blindness and retinitis pigmentosa, respectively.

2.1.1 Congenital stationary night blindness / stationary rod diseases

As the name implies, congenital stationary night blindness (CSNB) is a non- progressive visual impairment present at birth. However, it is also one of the first symptoms in progressive diseases, including retinitis pigmentosa (RP). Therefore, a differential diagnosis by genetic testing can provide helpful and important information to the affected individuals and families, in order to exclude or confirm the clinical diagnosis and to provide counselling.

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

CSNB is heterogeneous in clinical and genetic terms. Currently, 11 genes are known to carry sequence alterations or mutations, which are associated with this disease

(Figure 2, Table 1) (Audo et al., 2009; Bech-Hansen et al., 1998; Bech-Hansen et al.,

2000; Dryja et al., 1993; Dryja et al., 1996; Dryja et al., 2005; Fuchs et al., 1995; Gal et al., 1994; Li et al., 2009; Pusch et al., 2000; Strom et al., 1998; van Genderen et al., 2009; Wycisk et al., 2006; Yamamoto et al., 1997; Zeitz et al., 2005; Zeitz et al.,

2006). Mutations in these genes can be dominant, recessive or X-linked. With respect to clinical manifestations, several forms can be distinguished: Schubert

Bornschein type of CSNB, the complete and the incomplete type of CSNB, and

CSNB with fundus abnormalities. One of the most important diagnostic tools to discriminate the different clinical types is the electroretinogram (ERG), which measures the response of different retinal cell types to light. Schubert Bornschein

CSNB shows a negative scotopic (dim light conditions) ERG, with normal a-wave

(photoreceptor response) amplitude that is larger than that of the b-wave (bipolar cell and second order neuron response). Also, dark adaptation of rods is reduced drastically or even completely absent, while cone adaptation thresholds are variably elevated in most patients. There are two types of CSNB with regard to ERG characteristics: (i) the Riggs type with an absent rod and reduced cone response in the ERG and (ii) the Schubert Bornschein type with a so-called negative ERG under scotopic conditions. The Nougaret type of CSNB, which has been described in a large French family, is characterized by the Riggs type ERG and autosomal dominant inheritance. The disease was found to be due to mutations in the alpha subunit of transducin (Dryja et al., 1996). The Schubert Bornschein disease can be subdivided in (i) CSNB1 or complete CSNB and (ii) CSNB2 or incomplete CSNB. In CSNB1, the rod b-wave is significantly reduced or absent, while that of the cones is largely

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

normal. In the incomplete type of CSNB, both the rod and the cone b-wave amplitudes are reduced (Zeitz, 2007).

The functional spectrum of genes involved in CSNB contains calcium channel subunits (CACNA1F, CACNA2D4, TRPM1), a calcium binding protein (CABP4), a metabotropic glutamate receptor (GRM6), but also molecules of the phototransduction cascade (GNAT1, GRK1, PDE6B, SAG, RHO) as well as proteins of unknown function (NYX). Interestingly, mutations in Rhodopsin and the beta subunit of the rod phosphodieasterase can lead to stationary and progressive retinal diseases. While most of the mutations in the RHO gene lead to autosomal dominant or recessive RP (see below), a few amino acid substitutions have been described which lead to stationary night blindness (Figures 2 and 6) (al Jandal et al., 1999;

Dryja et al., 1993; Rao et al., 1994; Sieving et al., 1995; Sieving et al., 2001; Zeitz et al., 2008). The respective mutations may lead to a constitutively active signal transduction at a relatively low level, which makes affected rod photoreceptor cells less sensitive to low light intensities. This has been shown for rhodopsin mutations

(Sieving et al., 2001; Zeitz et al., 2008). The missense mutation c.884C>T

(p.Ala295Val) in rhodopsin was found in a Swiss family with autosomal dominant

CSNB. It was characterized in a functional assay, where the catalytic GTP exchange of transducin was measured. In the presence of 11-cis retinal, the respective mutant rhodopsin was found to be inactive, similar to wild-type. Contrary, in the absence of

11-cis-retinal, unlike wild-type opsin, the mutant opsin constitutively activated transducin (Zeitz et al., 2008). Because of this constitutive activity, the affected individuals experience decreased sensitivity to light.

In addition to this defect in rod photoreceptor cells themself, signal transmission between photoreceptors and the respective bipolar cells may be disturbed or even eliminated by mutations in different genes. The calcium channel subunits or the

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

metabotropic glutamate receptor mGluR6/GRM6 are interesting molecules to study and for understanding the complex interactions between photoreceptor and bipolar cells (Dryja et al., 2005; Zeitz et al., 2005).

2.1.2 Retinitis pigmentosa and progressive rod cone diseases

The term retinitis pigmentosa (RP) describes a group of clinically similar phenotypes associated with genetically heterogeneous causes. The disease onset and progression may vary significantly among patients, even within the same family. The patients frequently experience night blindness in the early phase of the disease, followed by loss of vision starting in the midperiphery and progressing towards the center which results in tunnel vision (Hamel, 2006). On the cellular level, these phenotypes correlate with a predominantly affected rod photoreceptor system. In later stages, the disease may further affect the cone photoreceptors eventually causing complete blindness. The diseased photoreceptors undergo apoptosis which is reflected in reduced outer nuclear layer thickness within the retina, as well as in lesions and/or retinal pigment deposits in the fundus. Patients may loose a significant portion of their photoreceptors before experiencing loss of visual acuity (Geller et al.,

1993). To assess the disease status and progression, electroretinographic measurements provide a sensitive method (Berson, 1993). In contrast to CSNB, which predominantly affects the b-wave, RP is characterized by reduced or absent a- and b-waves in the ERG.

The prevalence of RP is estimated to be about one in 3500 individuals (Hartong et al.,

2006). After the first report about linkage of an RP locus to a DNA marker on human chromosome X twenty six years ago (Bhattacharya et al., 1984), over 40 genes have been associated with RP (Figure 2, Table 2). Disease causing mutations may be inherited autosomal recessive (Abd El-Aziz et al., 2008; Banerjee et al., 1998; Bareil

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

et al., 2001; Collin et al., 2008; den Hollander et al., 1999; Dryja et al., 1995; Gal et al., 2000; Huang et al., 1995; Martinez-Mir et al., 1998; Maw et al., 1997; Maw et al.,

2000; McLaughlin et al., 1993; Morimura et al., 1998; Nakazawa et al., 1998; Rivolta et al., 2000; Thompson et al., 2001; Tuson et al., 2004; Zangerl et al., 2006; Zhang et al., 2007b) or dominant (Abid et al., 2006; Bowne et al., 2002; Chakarova et al., 2002;

Chakarova et al., 2007; Farrar et al., 1991; Freund et al., 1997; Friedman et al., 2009;

Kajiwara et al., 1991; Kajiwara et al., 1994; Keen et al., 2002; Kennan et al., 2002;

McKie et al., 2001; Rebello et al., 2004; Sato et al., 2005; Vithana et al., 2001; Wada et al., 2001; Zhang et al., 2007a; Zhao et al., 2009), as well as X-linked (Meindl et al.,

1996; Roepman et al., 1996a; Roepman et al., 1996b; Schwahn et al., 1998).

Interestingly, mutations in several genes can be either dominant or recessive (Bernal et al., 2008; Bessant et al., 1999; Coppieters et al., 2007; Davidson et al., 2009;

Dryja et al., 1990; Morimura et al., 1999; Pierce et al., 1999; Sullivan et al., 1999).

The majority of cases (50-60%) are autosomal recessive, sporadic or simplex

(Hartong et al., 2006). Also, families with autosomal dominant (30-40%) and X-linked inheritance (5-20%) are frequently observed. Maternal (mitochondrial) inheritance is very rare in RP.

The functions of the different RP-associated genes may be grouped into mainly five categories: (i) phototransduction, (ii) retinal metabolism, (iii) tissue development and maintenance, (iv) cellular structure, and (v) splicing.

The splicing category will now be discussed in more detail. It is particularly interesting as it only contains genes that are widely expressed although the patients’ phenotype is restricted to photoreceptors in the retina. Around 10% of the RP-associated genes belong to this rather recently discovered category. The splicing-relevant gene products (PRPF3, PRPF8, PRPF31 and PAP1) are involved in the assembly of the

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

spliceosome, a basic component of the splicing machinery. The spliceosomal protein complex catalyzes the removal of intronic sequences from pre-mRNA transcripts.

Since the removal of introns is essential for almost all transcripts of the cell, it is intriguing that mutations in genes of the splicing category exclusively result in RP.

Possible explanations for this observation are: (1) Photoreceptors have specialized splicing machineries that make them more vulnerable to alterations in splice components than other cell types. (2) The splicing of photoreceptor-specific genes is selectively affected. (3) Due to specialized requirements (e.g. transcript turnover), photoreceptors depend more strongly than other cell types on efficient splicing.

Studies first supported possible explanation 2 and suggested that the removal of intron 3 of RHO is inhibited by the mutated splice factor PRPF31 (Yuan et al., 2005).

The authors expressed the mutated PRPF31 to detect the splice defect in RHO.

Subsequently, studies suggested that haploinsufficiency is the underlying mechanism for PRPF31 mutations, i.e. the mutated allele is not expressed and the reduced gene dosage causes the disease (support for possible explanation 3) (Rio et al., 2008).

Nevertheless, splicing of RPGR intron 9 has been found to be misregulated in patient-derived lymphoblastoid cell lines with PRPF31 mutations. In contrast, cell lines with PRPF8 mutations show more general splice defect of several transcripts

(Ivings et al., 2008). The latter findings suggest that different disease mechanisms underly RP caused by mutations in different splice factor genes.

Although the functional properties of several RP-associated genes have been extensively studied, genotype-phenotype correlations are incompletely understood.

Frequently, they are complicated by multiple clinical features caused by mutations in the same gene (Figure 6). This observation often involves the complex molecular

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

properties of a single RP gene. Subsequently, examples will be discussed to illustrate the problems associated with genotype-phenotype correlations.

RHO is among the most prominent RP-associated genes. RHO constitutes a 7- transmembrane receptor protein which initiates the phototransduction cascade upon absorption of light by its chromophore 11-cis-retinal. The vast majority of mutations show a classical autosomal dominant inheritance leading to RP, the mechanism of which is fairly well understood as being either a gain-of-function or a dominant negative effect of the mutated protein (Mendes et al., 2005). Nevertheless, few mutations show an autosomal recessive inheritance or lead to night blindness only.

Convincing models exist for RHO mutations associated with night blindness and have been discussed above. It is less clear why the missense mutation p.E150K in

RHO was found to cause RP only in a homozygous state, whereas heterozygous carriers developed no RP phenotype. This is indicative of a recessive inheritance pattern (Kumaramanickavel et al., 1994). It is well possible that these recessive RHO mutations constitute exceptionally mild mutations that are either tolerated by the photoreceptor or lead to RP late in live (Neidhardt et al., 2006). The same may apply to night blindness-associated mutations.

Overall, the progression of clinical symptoms in patients with RHO mutations seems milder compared to that in patients with RPGR mutations (Sandberg et al., 2007).

The reason for this clinical variability is not understood. RPGR is the major X-linked recessive RP gene and is frequently associated with mutations in male patients. Male to male transmission of the phenotype does not occur. Nevertheless, families with dominant inheritance pattern, as well as patients showing other forms of retinal degenerations have been reported (Figures 2, 3 and 6) (Ayyagari et al., 2002;

Demirci et al., 2002; Neidhardt et al., 2008). Also, there are a few examples of female carriers showing disease symptoms of variable degree (Banin et al., 2007; Li et al.,

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

2005; Rozet et al., 2002). This effect might be attributed to a dominant nature of some of the mutations or non-random X-inactivation in the affected tissue, which has not been proven so far. An interesting feature of the RPGR gene is the generation of large numbers of splice variants (Kirschner et al., 1999; Kirschner et al., 2001). The alternative exon ORF15 of RPGR is expressed predominantly in retina and is a hotspot for RP-associated mutations (Vervoort et al., 2000). ORF15 transcripts give rise to several splice variants (Hong et al., 2002). Nevertheless, mutations in ORF15 are almost exclusively frameshift or stop mutations that cause premature termination codons. Thus this exon is likely to play a crucial role for the function of RPGR in the retina. Interestingly, mutations at the 3’ end of exon ORF15 tend to result predominantly in cone over rod dystrophies rather than RP (Ayyagari et al., 2002;

Demirci et al., 2002; Moore et al., 2006; Ruddle et al., 2009; Shu et al., 2007; Walia et al., 2008; Yang et al., 2002). This indicates that functional properties of the 3’- or

C-terminal RPGR region are relevant for the survival of cones. Furthermore, the existence of alternative splice variants affecting this part of the gene complicates a clear genotype-phenotype correlation, but indicates that transcript processing is involved in the underlying pathogenic process. We provided further support for the observation that RPGR splice variants are relevant for the function of cones and showed that RPGR isoforms containing the alternative exon 9a are predominantly expressed in cones of the human retina (Neidhardt et al., 2007). Since splicing is tightly regulated and its mis-regulation has previously been associated with several diseases (Faustino et al., 2003), even mild alterations of the patients’ splice pattern might give rise to modifications of the phenotype (Schmid et al., 2010). Consequently, up or down regulation of tissue-specific RPGR isoforms might be responsible for a shift between different clinical expressions like RP and COD and might further influence the phenotype in heterozygous mutation carriers.

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

Also in mice, the phenotype is variable and depends on the genetic background. We have generated mutant mouse lines with an in-frame deletion of exon 4 of the Rpgr gene (Brunner et al., 2009). This mutation was introduced in two different inbred mouse lines: either C57BL/6 or BALB/c. On the BL/6 background, the phenotype is rod dominated while it is predominantly affecting cones in the BALB/c line.

Furthermore, mislocalization of rhodopsin and cone opsin is consistent with a function of Rpgr in transport mechanisms, as reported previously (Khanna et al.,

2005; Roepman et al., 2000). This functional property of Rpgr is also supported by our findings in transgenic mice with overexpression of the protein. We observed that male infertility was due to aberrant spermatozoa (Brunner et al., 2008). The associated flagellar phenotype was more severe in mice with a high copy number of the transgene compared to mice carrying less Rpgr copies. These findings further support a role of Rpgr in ciliary transport and show that it is not confined to the retina.

This also explains why RPGR mutations in patients can lead to a syndromic phenotype.

2.2 Cone and cone rod diseases (stationary and progressive)

As mentioned above, the cone photoreceptor cells in the human retina are responsible for daylight vision and are instrumental for high visual acuity and colour discrimination. A recent review about the structure and evolution of the cone system summarizes our current knowledge about this class of photoreceptor cells (Mustafi et al., 2009). Only 5% of photoreceptor cells are cones. A human retina contains approximately 60 million rods and 3 million cones. The cone system has a high spatial resolution but is less sensitive to light as compared to rods. During evolution, primates have acquired trichromatic colour vision. Other mammals, including mice, are dichromatic. The three cone types (red, green and blue) in humans are

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

designated L, M, and S cones according to their sensitivity to photons. The L cones are most sensitive to low frequency photons (555-565 nm), the M cones to middle frequency photons (530-537 nm), and the S cones to supra frequency photons (415-

430 nm). There are twice as many L than M cones and the S cones constitute only

5% of all cone photoreceptors.

The cone photoreceptor cells are not evenly distributed in primate retinas. The macular region and its centre, the fovea centralis, contain almost exclusively cones, except S cones, which are located more peripherally. The gene NRL, which codes for a transcription factor, plays a crucial role during photoreceptor differentiation and promotes the rod development while it suppresses the cone programme.

Human diseases that affect the cone system, such as macular or cone and cone rod degenerations, lead to severe visual impairment. Clinically, patients with these diseases have a decreased visual acuity, photophobia, nystagmus, and colour vision abnormalities. Night blindness occurs in later stages of the disease when the rod system also becomes affected. However, cone diseases can be stationary, e.g. the different forms of complete and incomplete achromatopsia.

2.2.1 Stationary cone dysfunctions

Stationary subtypes of cone dysfunctions are complete and incomplete achromatopsia. They are usually congenital. Affected individuals with complete achromatopsia show infantile nystagmus, poor visual acuity, photophobia and are unable to distinguish colours. Mutations in four genes can cause complete achromatopsia: CNGA3, CNGB3, GNAT2 and PDE6C (Figure 3, Table 1) (Chang et al., 2009; Kohl et al., 1998; Kohl et al., 2000; Kohl et al., 2002; Thiadens et al., 2009;

Wissinger et al., 2001). GNAT2 codes for the cone-specific form of transducin, an essential component of the phototransduction cascade. CNGA3 and CNGB3 code

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for the alpha 3 and beta 3 subunits of the cyclic nucleotide gated chanel and are responsible for the ultimate step of the phototransduction cascade in cone photoreceptors that leads to membrane hyperpolarization when the channel is closed.

PDE6C codes for the cone-specific alpha subunit of the cGMP phosphodiesterase. It plays a key role in the essential phototransduction cascade of cone photoreceptors and mutations were recently found in cone dysfunction diseases (Thiadens et al.,

2009).

Patients with incomplete or atypical achromatopsia retain residual colour vision. Their visual acuity is mildly better compared to that of individuals with the complete form of the disease. All other symptoms are identical in both forms of the disease. Mutations in three autosomal genes (CNGA3, GNAT2 and PDE6C) have been associated with incomplete achromatopsia (Figure 3, Table 1). While the affore mentioned diseases affect all three cone types, there is one X-linked recessive stationary disease that affects the red and green opsin genes and consequently only two types of cones.

The disease is designated blue cone monochromatism. This X-linked form of incomplete achromatopsia is associated with reduced visual acuity, nystagmus, and photophobia. The underlying gene defect involves the green (M) and the red (L) opsin genes on the human X chromosome (Nathans et al., 1986). Two disease mechanisms were proposed, which lead to a lack of functional opsin molecules:

Either a loss of transcription caused by a deletion of the locus control region (LCR) upstream of the genes or the presence of a hybrid gene due to an unequal crossing over of the highly homologous red and green opsin genes. The latter reduces the number of tandemly arrayed opsin genes on the X chromosome to a single hybrid gene.

Another stationary cone disease, designated oligocone trichromacy, presents with reduced visual acuity, mild photophobia, a reduced amplitude in the cone ERG but

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

normal colour vision (Andersen et al., 2009; Michaelides et al., 2004). A reduced number of foveal cones may be responsible for this disease. So far, mutations in the genes encoding the cone-specific transducin alpha subunit (GNAT2) and the beta 3 subunit of the cyclic nucleotide gated channel (CNGB3) were associated with this form of cone dysfunction (Andersen et al., 2009; Rosenberg et al., 2004).

2.2.2 Cone and cone rod dystrophies (CODs and CORDs)

The age of onset for CODs or CORDs is usually during childhood or early adult life.

The progressive cone diseases are generally more severe than the progressive rod dominated phenotypes (e.g. RP). Although some peripheral vision is preserved, it can lead to legal blindness earlier than RP. Affected individuals experience first symptoms of decreased visual acuity at school during the first decade of life. In addition, patients with progressive CODs and CORDs feel intense photophobia and variable degrees of colour vision abnormalities. Central scotomas can be also present upon visual field testing. The fundus examination frequently reveals pigment deposits and retinal atrophy in the macular region. To discriminate CORDs from

CODs and macular degeneration, additional ophthalmologic examinations are needed (fluorescein angiography, fundus autofluorescence, ERG). In contrast to

CODs, CORDs show a peripheral retinal involvement and the ERG is characterized by a decrease in both cone and rod responses. However, cone responses are more severely affected than the rod-specific ERG components. In pure CODs or early

CORDs, scotopic ERG is normal. In later disease stages, night blindness occurs and the loss of the peripheral visual field is progressing. This is different in rod dominated retinal diseases, where night blindness is one of the first symptoms and the disease progresses from the periphery to the centre.

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

Currently, about 20 different genes have been shown to carry mutations that cause non-syndromic progressive cone disease (Figure 3, Table 3). The mode of inheritance is either autosomal dominant, recessive, or X-linked.

2.2.3 Macular degenerations (monogenic and AMD)

The macula, a region of the retina with high density of cone photoreceptors, can undergo specific degenerative processes, called macular degeneration. In this review, we discuss the classic monogenic forms of macular degeneration but also the multifactorial, age-related form of this disease.

The heterogeneous clinical features of macular dystrophies include a progressive loss of visual acuity, colour vision abnormalities, and central scotomas. The disease can manifest early or late in life. The typical and very frequent age-related form of macular dystrophy is not a classic monogenic disease but involves a complex interaction of multiple genetic components and environmental factors.

Patients with macular degenerations usually show a normal or only slightly reduced electrophysiologic response upon ERG and EOG testing. This is different to more generalized or severe cone as well as rod dominated diseases, which show a significant reduction of the a-wave amplitude in the scotopic ERG and can be used as a characteristic feature for differential diagnosis. Full field ERG is often normal, even if the patients are legally blind due to a macular degeneration. Application of a more sensitive method, multifocal ERG, allows measurements by recording electrophysiologic responses from hundreds of small retinal areas simultaneously within less than 10 minutes per eye (Marmor et al., 2003). With this method, scotomas of only a few millimeters in diameter can be identified and accurate quantification of the extent of retinal dysfunction is possible.

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

2.2.3.1 Monogenic macular dystrophies

Monogenic macular dystrophies can occur as a part of a multiorgan disease (e.g.

Alport syndrome, BBS, Refsum disease) or in non syndromic forms. The mode of inheritance can be dominant, recessive, or X-linked. However, most of the mutations show a dominant effect. Currently, more than 10 genes have been identified which carry pathogenic sequence variants in patients with macular degenerations (Figure 3,

Table 4a).

Mutations in the ABCA4 gene, which encodes an ATP-binding cassette transporter, can lead to a variety of retinal degenerative diseases, including juvenile macular degeneration (Stargardt disease), RP, as well as cone or cone rod dystrophy

(Allikmets et al., 1997; Briggs et al., 2001; Cremers et al., 1998; Fishman et al., 2003;

Kitiratschky et al., 2008; Maugeri et al., 2000; Rozet et al., 1998). The combination of these different clinical entities has been observed even within a family (Klevering et al., 2004a). This might be due to the high frequency of ABCA4 mutation carriers in the general population (about 5%) (Maugeri et al., 1999). The ABCA4 gene encodes a membrane protein of the rod and cone photoreceptor outer segment disks (Sun et al., 1997). The gene consists of 50 exons and the open reading frame contains 2273 amino acid residues. ABCA4 mutations may show variable expressivity of the phenotype. They can lead to COD, CORD, MD, or RP (Figures 2, 3 and 6, Tables 2,

3, 4a and 4b).

The variable expressivity of mutations in a single gene is also observed for peripherin

(PRPH2) (Figures 2, 3 and 6, Tables 2, 3 and 4a). In the vast majority of cases, mutations are dominant and can lead to RP, pattern dystrophy, fundus flavimaculatus, vitelliform macular dystrophy, or cone rod dystrophy (Felbor et al., 1997; Kajiwara et al., 1991; Keen et al., 1994; Nakazawa et al., 1994; Weleber et al., 1993). PRPH2 mutations were also shown to be responsible for digenic RP (Kajiwara et al., 1994).

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This form of RP is caused by mutations in ROM1 and PRPH2 and only double heterozygotes develop disease symptoms. Variability of clinical manifestations of

PRPH2 mutations was also observed within the same family (Apfelstedt-Sylla et al.,

1995).

2.2.3.2 Age-related macular degeneration (AMD)

As the name indicates, this form typically affects the elder population. Not only age but also hypertension, smoking, diet, obesity and chronic inflammation have been discussed as environmental risk factors (Ambati et al., 2003). Based on twin and family studies, convincing data have been collected that show a substantial contribution from genetic constitutions of the individual (reviewed by (Chamberlain et al., 2006; Patel et al., 2008)).

AMD has a prevalence of 0.05% before the age of 50 years, which increases to about 12 % in a population older than 80 years of age. With a general tendency of an aging population, this condition of vision loss will cause an increasing amount of individual discomfort and associated costs (Augood et al., 2006; Javitt et al., 2003;

Klaver et al., 2001). Ethnic barriers to attract the disease have not been described but differences in the severity of the clinical appearance are recognized.

Several reviews provide different aspects of the progression in the field of AMD

(Chamberlain et al., 2006; Edwards et al., 2007; Haddad et al., 2006; Lotery et al.,

2007; Patel et al., 2008; Scholl et al., 2007; Swaroop et al., 2007; Tuo et al., 2004).

We would like to discuss here the genetic heterogeneity and its impact on the complexity of AMD. The etiology of AMD differs from that of the monogenic forms of macular degenerations, which is also reflected by the fact that a combination of multiple genetic loci (Table 4b) but also environmental circumstances are responsible for the development of AMD (Patel et al., 2008; Scholl et al., 2007). In the age-

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related form one can observe abnormalities of the retinal pigment epithelium (RPE) as well as the formation of characteristic deposits containing lipids and proteins, designated drusen. In general, two different types of AMD can be distinguished: (i) an exudative or wet form of AMD and (ii) a non-exudative or dry form. The latter can transform to an exudative form, which is found in about 15% of all patients. In this form of AMD choroidal neovascularization (CNV) develops, which tends to cause vessel leakage and consequently bleeding occurs. The drusen can vary greatly in their position, number and size. This phenotypic variability has contributed to the difficulties of recognizing a straight phenotype-genotype correlation.

To identify genetic determinants involved in complex diseases, several approaches have been taken. The candidate gene approach has focused primarily on three aspects: (i) genes which had previously been identified in monogenic macular degenerations ; (ii) candidate genes which were chosen based on their function and

(iii) genes within regions identified through linkage studies (Chamberlain et al., 2006;

Patel et al., 2008; Scholl et al., 2007). Due to limited access to large families and the uncertainty of a genetic model, association studies became more promising than linkage analyses, in particular with the availability of increased numbers of genetic markers (single nucleotide polymorphisms, SNPs) and therefore increased power of analysis, despite a small sample size. In this review, we will focus on the understanding we have gained from studying candidate genes that can predispose to

AMD.

The role of the immune system in AMD

The complement system is part of the innate defense mechanism. A large number of proteins (about 30) participate in a cascade reaction of which three different pathways have been described: the classical, the alternative and the lectin pathway.

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The cascade can be inhibited by the complement factor H (CFH), a component of the alternative pathway. Uncontrolled activation of the system may lead to the formation of drusen (Sivaprasad et al., 2006). Histological analysis of the retina of AMD patients allowed the detection of many components of the complement system within these structures (Hageman et al., 2001). Assessment of the frequency of the p.Y402H variant, (c.1277T> C) (SNP rs1061170) of CFH in AMD patients compared to control populations allowed the identification of the first risk locus (odds ratios ranging between 4.54 and 11.61 in homozygous individuals) (Edwards et al., 2005;

Haines et al., 2005; Klein et al., 2005; Zareparsi et al., 2005). Individuals that carry the histidine variant at position 402 of the protein are at approximately 50% risk to develop AMD, either the form of geographic atrophy or the exudative, neovascular form (Patel et al., 2008). Accordingly, non-carriers may experience protection against

AMD. Environmental risks, such as smoking and body mass index, do not appear to increase the risk in combination with the CFH sequence variants (Lotery et al., 2007).

In contrast, ethnic origin was reported to have a modifying effect (Lotery et al., 2007).

Since amino acid position 402 lies within a region of CFH that interacts with heparin and C-reactive protein (CRP) (Giannakis et al., 2003) it was suggested that altered binding to these components on the outer retinal surface could affect the level of inflammation and consequently affect the development of AMD (Edwards et al., 2005;

Haines et al., 2005; Klein et al., 2005). Spurred by this initial report, several other studies confirmed the association of CFH with AMD. A meta-analysis indicated a multiplicative genetic model with each risk allele increasing the odds of AMD by approximately 2.5 fold (Thakkinstian et al., 2006).

While the CFH p.Y402H variant is associated with AMD in Caucasian (Conley et al.,

2005; Hageman et al., 2005; Kim et al., 2008; Maller et al., 2006; Narayanan et al.,

2007; Scholl et al., 2008; Seddon et al., 2009; Zareparsi et al., 2005) and Chinese

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populations (Lau et al., 2006), it was not found in Japanese patients with exudative

AMD (Gotoh et al., 2006). Several factors may explain population differences: first, different allele frequencies (the C allele frequency is 0.282 in Caucasian population

(HAP-MAP CEU) and 0.057 in Japanese population (HAP-MAP JPT); Ref: NCBI May

2008); second, the prevalence of late stage AMD is higher in Caucasians compared to Japanese population (Oshima et al., 2001) and third, formation of drusen is less frequent in Japanese patients (Bird, 2003). Interestingly, the C allele is significantly associated with the risk for AMD (odds ratio of 4.4) in the Han-Chinese (Beijing) population, despite its only slightly higher frequency (frequency: 0.067) (Lau et al.,

2006). Whether the C-allele is associated with both forms of advanced AMD in the

Chinese population is not yet clear since only the neovascular form of AMD was tested.

Complement factors CFB, C2 , C3 and C5 are further components involved in the activation of the alternative pathway. CFB and C3 products were shown to accumulate in drusen and Bruch’s membrane of AMD patients and genetic variants for CFB and C2 confer increased risk (Odds ratio of 1.32) as well as protection (Odds ratio 0.36 and 0.45) (Gold et al., 2006). These data have been confirmed in a replication study (Spencer et al., 2007). By conferring reduced hemolytic activity, the p.R32Q variant of CFB could contribute to the protective function (Gold et al., 2006;

Spencer et al., 2007). Furthermore, the absence of CFH-related genes CFHR1 and

CFHR3 is also associated with protection against AMD (Hughes et al., 2006). While no association was found with variants in the C5 locus, the non-synonymous change p.R102G in C3 was associated with both, the dry and wet form of AMD ( GR/RR: odds ratio 1.61; GG/RR odds ratio 3.26) (Maller et al., 2007). This association was independently confirmed in another Caucasian population (Spencer et al., 2008).

The possibility of interaction between the C3, CHF, CFB and C2 components could

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not be confirmed (Maller et al., 2007). Since complement C1 activates components

C2 and C4, inhibition of C1 leads to alteration of the complement cascade. DNA sequence variants in the SERPING1 gene, which codes for the serine protease family member serpin peptidase inhibitor, clad G, confer a protective effect on AMD, regardless whether patients are affected by choroidal neovascularization (CNV) or geographic atrophy (GA) (Ennis et al., 2008). Failure to replicate these findings in a different patient cohort (Park et al., 2009) may reflect a cohort-specific effect.

Taken together, convincing evidence has been presented over the last four years showing that sequence alterations in components of the complement cascade contribute significant effects on the risk to develop AMD. Sequence variants in some of them might provide protection against AMD development.

Perturbation of the signaling cascade leading to inflammation has also been proposed to cause susceptibility to AMD (Ambati et al., 2003; Donoso et al., 2006).

Within this context, the G allele (c.1063A>G) of the toll-like receptor 4 (TRL4), a bacterial endotoxin receptor, increases the risk of developing either the dry or wet form of AMD within a Causasian population (odds ratio around 2.65) (Zareparsi et al.,

2005). In addition, TRL4 participates in the phagocytosis of photoreceptors, a process which is important during the normal visual cycle and if perturbed, may lead to AMD. Another Toll-like receptor gene, TRL3, which encodes a viral sensor that supports the innate immune defense system could be associated with protective function of a coding variant in AMD with geographic atrophy (odds ratio for the T allele at SNP rs3775291 ranged between 0.198 and 0.712) but not with the neovascular or early form (Yang et al., 2008b). Whether double stranded viral RNA, the substrate for TRL3, does in fact exist in the eye, remains to be investigated. In general, Yang and colleagues propose that this protective effect may be due to suppression of RPE cell death. In an earlier study Edwards and colleagues reported

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only marginal association of variants in TRL3, TRL4 and TRL7 with AMD (Edwards et al., 2008). It is noteworthy, that the number of patients with geographic atrophy was relatively small (16% of 396 AMD patients) and may have diluted the association results for the dry form of AMD.

The role of the stress response in AMD

A link between the immune response contributing to AMD and oxidative stress damage was proposed from studies in mice (Hollyfield et al., 2008). It was hypothesized that Increased oxidative stress may lead to an increase in modified low-density lipoprotein, which in turn can be inhibited by paraoxonase (Mackness et al., 1993). This enzyme is encoded by the gene PON1, of which two variants in the protein coding sequence of the gene were shown to be associated with AMD in a

Japanese population (Chi square: 6.226 and 6.863 with P=0.445 and 0.323, for the two variants respectively) (Ikeda et al., 2001). The attempt to replicate these findings in a patient cohort from Australia failed (Baird et al., 2004). Different allele frequencies together with differences in the AMD phenotype between these populations might be the reason (Bird, 2003; Oshima et al., 2001).

Another stress response protein, serine pronase encoded by the HTRA1 gene on chromosome 10q26, is expressed in the retina and the RPE and found at elevated levels in drusen (Yang et al., 2006). HTRA1 is involved in the regulation of degradation of extracellular matrix proteoglycans and binds to transforming growth factor beta, which in turn regulates extracellular matrix deposition and angiogenesis

(Oka et al., 2004). Lotery and Trump speculated that overexpression may alter the integrity of Bruch’s membrane, allowing the invasion of vasculature (Lotery et al.,

2007). These features and its location to a previously mapped risk region on chromosome 10 made HTRA1 a candidate for conferring an effect on the likelihood

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to develop AMD, and in fact sequence variant rs11200638 in the promoter of HTRA1 confers a risk for AMD in Caucasian and Chinese populations. The SNP rs10490924 in the nearby ARMS2 (LOC387715) locus is also associated with an increased risk for AMD. Since the two loci are in tight linkage disequilibrium it is difficult to determine the relative contribution for each variant (odds ratios range between 2.7 and 11.14) (Dewan et al., 2006; Jakobsdottir et al., 2005; Rivera et al., 2005; Weger et al., 2007; Yang et al., 2006). Recently, an insertion/deletion polymorphism near the 3’end of the ARMS2(LOC387715) locus was found to affect polyadenylation of its transcript (Fritsche et al., 2008). ARMS2 encodes a mitochondrial protein that localizes to the ellipsoid region of the photoreceptors and may as such confer risk to develop AMD (Fritsche et al., 2008). Furthermore, microsomal glutathione-S- transferase 1 (MGST-1) is part of the oxidative stress pathways and was implicated to play a role in AMD (Maeda et al., 2005) but no association with AMD was found

(Haines et al., 2006).

Vasculogenesis and angiogenesis

The exudative form of advanced AMD is characterized by neovascularization and hence it seems reasonable to search for genes that are involved in this process and may carry variants which influence the development of wet AMD (Grisanti et al.,

2008). Vascular endothelial growth factor (VEGF) encodes a homodimeric glycol protein, specifically produced by endothelial cells. It is a critical regulator of vasculogenesis and angiogenesis and involved in the induction of permeability of blood vessels. In addition VEGF is also required for normal maintenance of the vasculature. Among the different members of the VEGF gene family, VEGF-A is the most abundantly expressed and its nine different isoform are a result of differential splicing. The VEGF-A 120 variant is the target of treatment with anti-VEGF

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antibodies (Macugen, Ranibizumab (Lucentis) and Bevacizumad (Avastin) of patients with the wet/exudative form of AMD (Pieramici et al., 2008). Hypoxic conditions

(Fruttiger, 2007) as well as an imbalance of angiogenic and anti-angiogenic factors

(an example is pigment epithelium derived growth factor (PEDF)) can lead to retinal or choroidal neovascularization (Bhutto et al., 2006). In a family-based and a case control data set, DNA variants in VEGFA were shown to be associated with AMD

(Haines et al., 2006). In addition, a haplotype including nine DNA sequence variants in the promoter of VEGFA also associates strongly with neovascular AMD within a population of northern European origin (odds ratio of 18.24) (Churchill et al., 2006).

Furthermore, association was also found in an AMD patient population from Taiwan with a sequence variant in the 3’UTR of VEGFA (Lin et al., 2008). Other attempts to replicate association with VEGFA have failed, including the Rotterdam study

(Boekhoorn et al., 2008; Richardson et al., 2007). Heterogeneity in the patient populations could account for these inconsistent findings. Nevertheless, further investigations are required to fully understand the complexity of VEGFA involvement in the exudative form of AMD.

In summary, the search for susceptibility loci has contributed a substancial number of genes implicated in contributing to the risk of developing AMD but also with protective effects. As approximately half of the number of genes studied yield conflicting findings (Table 1 in reference Lotery and Trump (Lotery et al., 2007) further components influencing AMD remain to be identified.

2.3 Generalized photoreceptor diseases (non-syndromic)

2.3.1 Leber congenital amaurosis (LCA)

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The retinal dystrophy designated Leber congenital amaurosis (LCA) is the most severe in terms of visual loss and has a very early age of onset (<1 year of age). The clinical features include congenital or early onset loss of vision, sensory nystagmus and no light response upon electrophysiology (ERG). The frequency of the disease is about 1 in 50000. The genetic heterogeneity of this disease is considerable.

Currently, 15 genes were identified to carry mutations in patients affected by this disease (Figure 4, Table 5). The mode of inheritance of most of the mutations is autosomal recessive. Dominant inheritance is discussed for sequence alterations in

CRX and IMPDH1. Functionally, the different gene products are involved in many cellular functions including photoreceptor development and differentiation, phototransduction, vitamin A metabolism and others. Recently, a review has been published which summarizes clinical, genetic, diagnostic and also functional details about this group of diseases (den Hollander et al., 2008). Because of the recessive nature of most mutations, genetic homozygosity mapping is a particularly successful approach in order to identify the underlying molecular basis of the disease within families.

One of the genes which is associated with LCA was designated RPE65 (Marlhens et al., 1997). It encodes a protein consisting of 533 amino acid residues with high abundance in the retinal pigment epithelium. The protein is an isomerase and involved in the conversion of all-trans retinol to 11-cis retinal. Gene transfer of the

RPE65 gene in the eyes of patients provides the first example for a successful gene therapy in human patient with this severe form of retinal dystropohy (Bainbridge et al.,

2008; Hauswirth et al., 2008; Maguire et al., 2008), which is further described below.

2.3.2 Choroideremia

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Choroideremia (CHM) is an X-linked inherited retinal degeneration with an estimated incidence rate of 1: 50,000. Symptoms begin with night blindness during teenage years and the disease progressively affects degeneration of photoreceptor cells, retinal pigment epithelial cells, the choriocapillaris and the choroid, leading to complete blindness. This disease is caused by mutations in the REP1 gene

(Cremers et al., 1990; Merry et al., 1992), which encodes Rab escort protein-1. It mediates prenylation of Rab GTPases and affects their involvement in intracellular vesicular transport (Preising et al., 2004; Seabra et al., 1993). Among the numerous reported mutations (McTaggart et al., 2002), which cause frameshift, nonsense or splice site alterations, no missense mutations have been found. In contrast to mutations that affect only the REP1 locus leading to non-syndromic CHM, large gene deletions are known to cause syndromic phenotypes ((Poloschek et al., 2008) and references therein). Although the gene is ubiquitously expressed, mutations affect primarily retinal structures (Seabra et al., 2002). Expression of REP2 can compensate for the loss of functional REP1, except in the ocular structures, which leads to the specific eye phenotype (Cremers et al., 1994). This hypothesis is supported by the recent finding that nonmammalian vertebrates do not have the

REP2 gene and hence REP1 mutations are lethal (Moosajee et al., 2009). The disease-causing mechanism is still unclear but two models are discussed: a cascade type effect on the three layers photoreceptors, RPE and choroids, or an independent degeneration of them (Tolmachova et al., 2006).

2.3.3 Gyrate atrophy of the choroid and retina

Gyrate atrophy or ornithine aminotransferase deficiency, a slowly progressive chorioretinal degeneration, is inherited in an autosomal recessive pattern. The ocular symptoms include night blindness, myopia and a progressive loss of peripheral vision

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in the first decade of life, posterior subcapsular cataracts in the second and blindness in the fourth to fifth decade. There might be a mild skeletal muscle weakness and mental retardation but these extraocular symptoms are present only occasionally. An arginine restricted diet (arginine is the precursor of ornithine) has been described to be beneficial in some patients. However, the slow progression of the disease makes it difficult to quantify the effect of treatment. The disease is caused by mutations in the ornithine aminotransferase gene (OAT) on human chromosome 10 (Valle et al.,

1977). The disorder appears to be very rare with a higher incidence in Finnland (1 affected individual in 50000). The first mutation in this gene has been reported more than twenty two years ago (Mitchell et al., 1988).

2.4 Vitreoretinopathies

2.4.1 Erosive vitreoretinopathies

This group of rare diseases encompasses pathological appearance of the vitreous associated with retinal changes that may include the retinal pigment epithelium. We count several hereditary diseases to this group which are traditionally known as

Stickler syndrome, snowflake vitreoretinal degeneration, Goldmann-Favre syndrome, autosomal dominant vitreoretinochoroidopathy (ADVIRC), Wagner syndrome and erosive vitreoretinopathy (ERVR) (Figure 5, Table 6). Due to most recent molecular data, the latter two are now known as VCAN-related vitreoretinopathies (reviewed in

(Kloeckener-Gruissem et al., 2009). Vitreous syneresis, retinal changes with retinal detachment, development of cataract, poor night vision, visual field defects and abnormal ERG recordings, all of progressive nature, are clinical characteristics of these vitreoretinopathies. In most patients, first signs become obvious during the late teenage years. Restriction of visual acuity is among the first complaints of the patients. The affected vitreous is frequently described as “empty” with veils and

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strands. Except in autosomal dominant vitreoretinochoroidopathy, retinal detachment is a common accompanying feature of the phenotype. Clinically, the type of retinal detachment frequently allows the distinction between the different vitreoretinopathies.

While tractional detachment is the more typical type in Wagner disease and erosive vitreoretinopathy, the rhegmatogenous type of retinal detachment is characteristic for

Stickler syndrome and Snowflake vitreoretinal degeneration. In the following sections we aim to discuss the specific phenotypes with their underlying molecular basis.

Enhanced S-cone syndrome (ESCS)

ESCS patients show the rather unusual effect of gain of function of photoreceptors with varying degrees of severity of retinal degeneration. The more severe type is also known as Goldmann Favre syndrome (GFS). A liquefied vitreous body with preretinal band-shaped structures, development of cataract, macular changes like retinoschisis, pigment loss and a severely affected electroretinogram belong to the typical clinical picture in GFS patients. The retina displays areas with thickened layers localized to an annulus encircling the central fovea (Jacobson et al., 2004).

The patients have severely reduced numbers of rods and L and M type cone photoreceptors but simultaneously they show an increased numer of S cone photoreceptors (Milam et al., 2002). The molecular cause for this is most likely related to recessive mutations in the nuclear receptor gene NR2E3, which encodes a transcription factor whose expression pattern appears to be restricted to the outer nuclear layer of the adult retina (Haider et al., 2000). Either single nucleotide substitutions, in particular the R311Q substitution, or small deletions affecting the coding region lead to an altered function of the transcription factor (Milam et al.,

2002). Patients carry either homozygous mutations or are compound heterozygous

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(Lam et al., 2007). Interestingly, all mutations map to evolutionary conserved protein domains (Haider et al., 2000). Probably, mutations in NR2E3 cause abnormal cell fate during development of the retina, leading to an excess of S-cones at the expense of rods and L and M cones. In addition, a donor retina from a patient carrying the R311Q mutation displayed severe structural disorganization such that the cones were densely packed and interspersed with inner retinal neurons (Milam et al., 2002). It remains subject to speculation how mutations in NR2E3 relate to the vitreous syneresis typically found in GFS.

Snowflake vitreoretinal degeneration

The pattern of inheritance of this disease is also autosomal dominant. Patients show early onset cataract, vitreoretinal dystrophy, fibrillar degeneration of the vitreous and peripheral retinal abnormalities including shiny crystalline-like deposits resembling snowflakes. Rhegmatogenous retinal detachment is observed. The first family with snowflake vitreoretinal degeneration was originally described by Hirose et al (Hirose et al., 1974) with a follow up description (Lee et al., 2003). Using DNA from affected and unaffected members of this family a mutated nucleotide (c.484C>T, p.R162W) of the gene KCNJ13 on chromosome 2 was found to segregate with the phenotype.

KCNJ13 encodes Kir7.1, member 13 of subfamily J of the potassium inwardly rectifying channel family (Hejtmancik et al., 2008). Transcript analysis of KCNJ13 demonstrated expression in kidney and brain and within the eye in adult and neural retina and RPE cells (Yang et al., 2008a). The mutation (484C>T, R162W) disrupts the structure of the channel, which is the most likely cause for the retinal phenotype.

Understanding the vitreous phenotype remains a challenge since the channel has not been shown to be a structural part of the vitreous (Hejtmancik et al., 2008).

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Autosomal dominant vitreoretinochoroidopathy (ADVIRC)

This rare disease was first described by Kaufmann et al. (Kaufmann et al., 1982).

Characteristic fibrillar condensation within the vitreous is not accompanied by the appearance of an optically “empty” vitreous, as described in patients with Wagner syndrome. Furthermore, retinal breaks, retinal detachment, systemic or skeletal abnormalities are also missing. Typical to this dease are the following features: a hyperpigmented band of cells at the peripheral retina which is punctuated with white opacities, the breakdown of the blood retinal barrier with retinal neovascularization, presenile cataract and occasionally choroidal atrophy. Disease progression is very slow (Kaufmann et al., 1982) but can be recognized by ERG measurements since younger patients display a normal pattern that becomes moderately abnormal later in life. Rod photoreceptor cells seemed more severely affected than cones (decreased amplitude of a- and b-wave). An abnormal electro oculogram suggested a defect at the level of the RPE. Mutations in the gene VMD2, which is expressed in the RPE, were found to cause ADVIRC (Yardley et al., 2004). VMD2 encodes bestrophin, a trans-membrane protein expressed in the RPE. It was first found to be involved in

Best disease (vitelliform macular dystrophy, which is described elsewhere in this review). All VMD2 mutations are exonic and were found to cluster, irrespective of the different diseases, to regions in the trans-membrane domains (Table 7).

Table 7: Neighboring VMD2 mutations cause different disease phenotypes.

Mutation Protein Disease Effect c.253T>C p.Y85H Best disease no effect on splicing c.256G>A p.V86M ADVIRC novel splice variants p.V89A Best disease p.V235L Best disease p.V235M Best disease c.707A>G p.Y236C ADVIRC novel splice variants p.T237R Best disease c.715G>A p.V239M ADVIRC novel splice variants c.727G>A p.T241N Best disease no effect on splicing

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To explain how the closely spaced missense mutations can result in these two different phenotypes, Yardly et al. hypothesized that splicing might be affected via exonic splicing regulatory elements (Yardley et al., 2004). This hypothesis could be verified by using an in vitro mini gene functional assay. Production of novel splice variants was specific only for those mutations causing ADVIRC, but not for the neighboring Best disease causing mutations. With this high degree of genotype- phenotype correlation the authors suggest that the abnormal splice products have a novel effect on ocular development (Yardley et al., 2004).

Wagner syndrome and erosive vitreoretinopathy

Wagner syndrome was first described in 1938 as a non systemic ocular abnormality

(Wagner, 1938). The clinical appearance of patients with Wagner syndrome includes syneresis of the vitreous, cataract, high myopia, night blindness and retinal detachment and has been reviewed recently (Kloeckener-Gruissem et al., 2009).

Linkage analyses revealed a region on chromosome 5 to which a candidate gene,

VCAN (formerly CSPG2), encoding the extracellular matrix protein versican, localized

(Brown et al., 1995; Perveen et al., 1999). It still took several years until the first causative mutation in VCAN was identified in a Japanese family with Wagner disease

(Miyamoto et al., 2005), which was followed by the identification of further mutations in the original Wagner family (Kloeckener-Gruissem et al., 2006) as well as in additional families (Meredith et al., 2006; Mukhopadhyay et al., 2006; Ronan et al.,

2009). All mutations localize to splice donor or acceptor sites that affect splicing of exon 8. VCAN is expressed in the vitreous and in cartilage and exists in four splice variants that differ in the presence or absence of exon 7 and exon 8. The levels of

VCAN variant V2 (no exon 8) and V3 (no exon 7) transcripts from patients’ blood or lymphoblastoid cell lines are highly elevated (Mukhopadhyay et al., 2006), indicating

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quantitative alterations of the naturally occurring splice variants as possible pathogenic mechanism.

A family with ERVR was also found to segregate a splice site mutation in VCAN

(Mukhopadhyay et al., 2006), suggesting that the two syndromes, Wagner and ERVR, are allelic, as it was previously anticipated based on mapping data (Black et al., 1999;

Brown et al., 1994; Brown et al., 1995; Mukhopadhyay et al., 2006). Diagnostic mutation screening can benefit tremendously from these findings as sequencing of the rather large exon 7 (2.961 kb) and exon 8 (5.262 kb) can initially be avoided by focusing on intron-exon sequences of exon 7 and exon 8.

2.4.2 Exudative vitreoretinopathies (EVRs)

EVR is characterized by an incomplete blood vessel development in the retinal periphery, as well as by retinal folds and retinal detachment. The clinical diagnosis is usually made in the first years of life. There may be a decreased visual acuity due to macular folds or detachment. Upon fluorescein angiography, the retinal periphery appears avascular. A fibrovascular mass may develop that is associated with retinal exudates. This mass may extend to the ciliary body and peripheral lens capsule. The clinical manifestations are highly variable and some patients do not experience dramatic visual impairment. The inheritance patterns include autosomal dominant and recessive as well as X-linked transmission of the mutations. Currently three genes are known to carry mutations (Figure 5, Table 6) but there might be additional genetic defects in other genes. The first gene identified in this disease is the X-linked

Norrie disease pseudoglioma gene (NDP) (Chen et al., 1993). Mutations in this gene lead usually to a severe disease, designated Norrie disease (ND) (Berger et al.,

1992a; Berger et al., 1992b; Berger, 1998; Chen et al., 1992; Meindl et al., 1992).

This disease is characterized by congenital blindness and progressive hearing

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impairment, starting in the first or second decade of life. In some cases, mental retardation or autistic features and behavioral manifestations are observed. Since mutations are X-linked recessive, only males are affected although exceptions exist, where female carriers also show symptoms (Sims et al., 1997; Yamada et al., 2001).

There is a wide spectrum of mutations in this gene (please refer to the following website, where more than 100 mutations are summarized: http://www.medmolgen.uzh.ch). Remarkably, the same amino acid substitution can lead to either classic Norrie disease or EVR. For example the mutation p.R121W results in classic or mild ND, but was also found in EVR (Kellner et al., 1996; Meindl et al., 1995; Shastry et al., 1995; Shastry et al., 1997a; Wu et al., 2007). The same amino acid substitution was reported to be associated with retinopathy of prematurity

(Shastry et al., 1997b), which is not a monogenetic trait but also might involve genetically predisposing factors.

Similar observations were reported in the literature for other amino acid substitutions in the NDP gene, for example p.I18K, p.R38C, p.K54N, p.K58N, p.R74C, p.C96Y and p.R121Q, all of which are associated with Norrie disease or EVR (Berger et al.,

1992b; Boonstra et al., 2009; Fuchs et al., 1996; Fuentes et al., 1993; Kondo et al.,

2007; Meindl et al., 1992; Meindl et al., 1995; Riveiro-Alvarez et al., 2005; Royer et al., 2003; Shastry et al., 1999; Shima et al., 2009). Because of the frequent reports of a variable clinical expressivity or manifestations of different mutations, it is difficult to predict the clinical course of the disease for a specific mutation.

In addition to NDP, three other genes were found to be mutated in EVR: Frizzled-4

(FZD4) (Robitaille et al., 2002), the low density lipoprotein receptor-related protein 5 gene (LRP5) (Jiao et al., 2004), and tetraspanin 12 (TSPAN12) (Nikopoulos et al.,

2010; Poulter et al., 2010). Similar to NDP mutations, pathogenic LRP5 sequence alterations also lead to extra ocular symptoms. The disease is designated

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osteoporosis pseudoglioma syndrome (OPPG). FZD4 mutations are dominant while

LRP5 mutations are recessive, although a bone phenotype can be present in LRP5 mutation carriers.

These four genes and their proteins are functionally linked. It was found that Norrin is a ligand of the receptor pair FZD4 and LRP5. Upon Norrin binding, the canonical Wnt signaling pathway is induced in the target cell (Xu et al., 2004). This was shown by using reporter gene assays in cell culture. The functional interaction of Norrin, FZD4,

LRP5 and TSPAN12 during retinal angiogenesis is also supported by phenotypic similarities observed in human patients but also in the respective mouse models

(Berger et al., 1996; Hsieh et al., 2005; Junge et al., 2009; Luhmann et al., 2005b;

Luhmann et al., 2005a; Luhmann et al., 2008; Schäfer et al., 2008; Wang et al., 2001;

Ye et al., 2009).

3. Syndromic retinal diseases

3.1 Usher syndrome

In Usher syndrome, not only the retina is affected by the disease but also the inner ear. The disease is a combination of retinitis pigmentosa (RP) and sensorineural deafness or hearing impairment. Clinically, Usher syndrome is classified in three subtypes, depending on the severity and age of onset of disease manifestations in retina and ear. The most severe form is Usher syndrome type 1. Patients with this subtype have profound and congenital deafness and vestibular dysfunction, leading to delayed motor development, and adolescent-onset RP. Usher type 2 is less severe with normal vestibular function, mild to severe sensorineural hearing loss, which is non-progressive in most cases, and a later onset of RP in adolescence or adulthood. Patients with Usher 3 also have a milder but progressive form of deafness and approximately 50% also manifest vestibular problems. The mode of inheritance

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for all three types of Usher syndrome is autosomal recessive. It accounts for approximately half of the cases of deaf-blind patients (Vernon, 1969) and affects between 1:12000 or 1:30000 people in different populations. The general frequency of RP is about 1 in 3000 to 1 in 5000 individuals, the Usher cases may represent between 10-30% of all autosomal recessive RP cases (Hartong et al., 2006). So far, mutations in 10 different genes (Figure 2, Table 8) have been associated with Usher syndrome (Bolz, 2009; Saihan et al., 2009; Williams, 2008). Two major loci for Usher type 1 and 2 are myosin 7A (MYO7A) and usherin (USH2A), respectively (Eudy et al.,

1998; Weil et al., 1995). MYO7A mutations account for 30-50% of Usher 1 cases.

The gene product is an actin-based motor protein. In addition to its motor domain, this exceptionally large protein (5202 amino acid residues) also contains additional domains which are responsible for the interaction with other cellular proteins and may be responsible for the intracellular transport of proteins through the connecting cilium of photoreceptor cells. This is supported by the abnormal accumulation of opsin within the connecting cilium in Myo7a-deficient mice (Liu et al., 1999). Usherin

(USH2A) is most likely a membrane anchored extracellular protein which is important for photoreceptor cell maintenance and proper development of sensory hair cells within the cochlea (Liu et al., 2007). The Usher-associated proteins form a complex network which is important for protein transport in photoreceptor and hair cells. Usher

1D (cadherin 23) and 1F (protocadherin-15) are cell adhesion molecules and might be important for the structural integrity of the tissue.

3.2 Bardet Biedl syndrome

Bardet-Biedl syndrome (BBS) is caused by mutations in at least 13 genes (see

Figure 2, Table 8) (Ansley et al., 2003; Badano et al., 2003a; Chiang et al., 2006; Fan et al., 2004; Katsanis et al., 2000; Li et al., 2004; Mykytyn et al., 2001; Mykytyn et al.,

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2002; Nishimura et al., 2001; Nishimura et al., 2005; Stoetzel et al., 2006; Stoetzel et al., 2007). The phenotypic variability among patients, even within one family, is significant. The primary features include retinal degeneration, obesity, polydactyly, renal and genital abnormalities, and learning disabilities. A number of secondary features, e.g. situs inversus, developmental delay, diabetes mellitus, and strabismus, have also been observed in BBS patients (compare www.geneclinics.org or

(Katsanis et al., 2001b)).

In a surprisingly short time period of around 8 years, 12 genes have been associated with BBS. This was even more surprising since the disease is rare and affects only 1 individual in 120000 Caucasians. Isolated populations with an increase in consanguinity accelerated gene identification using linkage or homozygosity mapping.

The first gene has been discovered in the year 2000 on the basis of linkage in

Newfoundland families. Linkage intervals suggested overlapping mapping positions with the clinically similar McKusick-Kaufman syndrome gene MKKS. Co-segregation of mutations in BBS6 patients within the MKKS gene confirmed that the two syndromes are allelic (Katsanis et al., 2000), but genetic heterogeneity suggested the existence of additional BBS genes. Combining classical genetic mapping technologies with an in silico-based method of comparing genomes of ciliated and non-ciliated species allowed the identification of BBS3, BBS5, and BBS9.

Furthermore, BBS7 as well as the causative gene within the BBS1 locus were discovered on the basis of protein homology with BBS2. Protein comparisons also lead to the identification of BBS8, which shows sequence similarity to BBS4.

Moreover, the predicted function of the gene product of BBS6/MKKS as a chaperonin-like molecule led to the identification of the most recently discovered

BBS-associated gene BBS12; the sequence homology to chaperonins indicated a priority for a candidate within the linkage interval of consanguineous families

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(Stoetzel et al., 2007). Moreover, BBS10 is also a possible chaperonin (Stoetzel et al.,

2006). Evolutionary conservation indicated that BBS 6, 10, and 12 are part of a separately evolved branch of the chaperonin gene family and thus might be involved in protein folding. Nevertheless, protein folding seems not to be the main function linking all BBS genes. A large body of work rather indicates that ciliary transport and basal body properties are disturbed in BBS patients. This observation is also supported by a number of clinical phenotypes, e.g. situs inversus (caused by disturbed ciliary function in the node of the developing embryo), as well as renal cysts (induced by dysfunction of cilia in the renal tubule or retinitis pigmentosa causes by inhibition of transport processes through the connecting cilium of the photoreceptor). Indeed, BBS1 is associated with vesicular transport processes of the cilium, indictated by the finding that BBS1 binds to Rabin-8 which in turn activates rab-8, a molecule that targets vesicles to cilia (Nachury et al., 2007). A similar process might also affect transport efficiencies across the photoreceptor connecting cilium and cause retinal degeneration. This hypothesis is supported by the finding that rhodopsin is less efficiently transported from the inner segment to the outer segment of rod photoreceptors in BBS2 knock out mice (Nishimura et al., 2004).

Furthermore, complexes containing chaperones, rhodopsin, and other photoreceptor- specific proteins have been associated to intraflagellar transport processes through the connecting cilium of rods (Bhowmick et al., 2009).

Disturbed transport processes across cilia may even influence basic cellular signaling cascades, as exemplified by the finding that a BBS4 knock down resulted in reduced inhibition of the canonical Wnt signaling pathways after stimulation with the Wnt effector Wnt3a (Corbit et al., 2008; Gerdes et al., 2007). However, the exact mechanism underlying the connection between cilia and Wnt signaling is not completely understood (He, 2008).

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Typically, BBS mutations are autosomal recessive. The most frequently mutated BBS gene is BBS1, which affects over 20% of the patients (Katsanis, 2004). Moreover, the hot spot mutation p.M390R is found in up to 80% of BBS1 patients (see www.geneclinics.org). The second most frequent hot spot mutation p.C91LfsX4 in

BBS10, which affects around 50% of the BBS10 alleles. Thus, a significant portion of the cases can be identified by screening only 2 exons in two BBS genes.

Nevertheless, 20-30% of the patients have no detectable mutations in the known genes (see www.geneclinics.org), which strongly indicates that further BBS genes await identification.

In some pedigrees the disease does not follow the classical autosomal recessive pattern, but seems to be transmitted in a digenic or oligogenic way. Individuals have been documented who showed two mutations in a single BBS gene in addition to a sequence alteration in a different BBS gene (Beales et al., 2003). Further support for the digenic or oligogenic inheritance is provided from individuals who carry two known mutations in BBS1 (p.M390R) without expressing the phenotype. Significantly, a case has been identified where only three nonsense mutations in two different BBS genes cause disease manifestations while two nonsense mutations on both alleles of a single gene do not lead to symptoms (Katsanis et al., 2001a). Nevertheless, in cases with oligogenic inheritance, the third mutation is often a missense mutation with uncertain pathogenicity. This may also indicate that additional mutations act as modifiers influencing the degree of phenotypic expression in patients (Badano et al.,

2003b). Consequently, different disease severities might be explained depending on the particular ‘BBS environment’ of the individual patient. The molecular basis for such ‘BBS environments’ has been reported (Nachury et al., 2007). Nachury et al. showed that seven BBS proteins build an interaction complex, called the BBSome.

Using BBS4 as bait, stoichiometric amounts of BBS1, BBS2, BBS5, BBS7, BBS8,

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and BBS9 have been isolated within a cilia-associated complex. Inhibition of members of the BBSome leads to disturbed ciliary properties. Thus, it may well be that additional mutations within the BBSome affect the phenotypic presentation of the respective patient. It will be interesting to further analyze these complex correlations, e.g. by crossing the homozygous BBS1 p.M390R knockin mouse model (Davis et al.,

2007) into different genetic backgrounds to determine the influence of modifiers for the disease expression. Alternatively, generating double or tripple knockout BBS mice might provide further clues to the genetic interaction between BBS genes and their consequences for the phenotype. In the light of modifier action or oligogenetic inheritance, it is interesting that while most BBS patients show severe retinal degeneration, mild forms have also been reported (Azari et al., 2006; Gerth et al.,

2008; Heon et al., 2005). In addition, different phenotypic expressions like retinitis pigmentosa and macular degeneration were reported in patients with a homozygous

BBS1 mutation p.M390R (Azari et al., 2006). This heterogeneity of the phenotype may be best understood through the action of genetic modifiers.

Analogous to the oligogenic influence on the BBS phenotype, other cases of RP or retinal degeneration are likely to be influenced by modifiers. As an example, mutations in the RPGR gene may cause X-linked recessive RP, but occasionally is associated with additional phenotypes like hearing defects, primary ciliary dyskinesia, or sinorespiratory infections (Iannaccone et al., 2003; Moore et al., 2006; Zito et al.,

2003). Furthermore, the disease expression largely varies even within one family.

Since RPGR binds a number of retinal degeneration-associated interaction partners at the molecular level (e.g. RPGRIP1, SMC1 and 3, CEP290 or Nephrocystin 5), it seems plausible that modifying sequence alterations affecting the ‘RPGR interactome’ would give rise to altered phenotypic severity or additional clinical manifestations.

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3.3 Senior Loken Syndrome / Nephronophthisis (SLSN)

Patients with SLSN manifest kidney and eye diseases. The kidney phenotype is designated nephronophthisis (NPHP) and the retinal degeneration can be RP of varying degrees or LCA, as in the case of NPHP6/SLSN6. So far, six genes were shown to carry mutations in affected individuals (Figure 2, Table 8). Recent studies have shown that the respective gene products are involved in the structure or function of motile and primary cilia. Therefore the term ´ciliopathies´ is also used for this group of diseases, as it is for primary ciliary dyskinesias. Most prevalent are mutations in the NPHP1/SLSN1 gene, which were found in approximately 20% of the families. All other genes are affected significantly less frequent (0.1-3%) (Hildebrandt et al., 2009). NPHP1/SLSN1 localized to the transition zone of the cilium and were found to interact with other proteins which can carry mutations in patients with Senior

Loken syndrome, including inversin, nephrocystin-3 and nephrocystin-4 (Fliegauf et al., 2006; Mollet et al., 2002; Olbrich et al., 2003; Otto et al., 2003). Although molecular diagnosis is possible in some families, the majority of cases

(approximately 70%) can not be explained by mutations in the genes known so far.

3.4 Refsum disease

Refsum disease belongs to the peroxisome biogenesis disorders (PBD), which also include Zellweger syndrome, neonatal adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata. The first symptoms may arise during late childhood and include defective night vision, progressive RP, mental retardation, and anosmia.

During disease progression additional features like polyneuropathy, deafness, ataxia, cardiac arrhythmias as well as skin abnormalities (ichthyosis) may establish. In addition, about one third of patients have bone manifestations in hand and feet

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(Jansen et al., 2004). Mutations in five genes were detected in affected individuals

(Figure 2, Table 8) (Furuki et al., 2006; Geisbrecht et al., 1998; Jansen et al., 2004;

Matsumoto et al., 2003; Shimozawa et al., 1999). The functional spectrum of these genes comprises fatty acid oxidation, peroxisomal protein import as well as peroxisome biogenesis.

3.5 Joubert syndrome

Joubert syndrome is a rare (1/100000) clinically and genetically heterogeneous group of developmental disorders, which is inherited in an autosomal recessive pattern.

One exception has recently been described with an X-linked recessive mode of inheritance (Coene et al., 2009). Characteristic features are hypoplasia of the cerebellar vermis with the neuroradiologic “molar tooth sign” and other neurologic symptoms including dysregulation of breathing pattern and a general developmental delay. Additional variable features which include polydactyly, hepatic fibrosis, renal disease and retinal dystrophy are often collectively referred to as cerebello-oculo- renal syndrome (CORS), which is also associated with primary ciliary dysfunction.

The clinical heterogeneity is reflected by genetic heterogeneity as eight genes have been described to be involved in Joubert syndrome (Figure 2, Table 8). Generally, mutations in one of the eight genes do not necessarily lead to all possible phenotypes. Mutations in the Abelson’s helper integration 1 gene (AHI1) also known as JBTS3 (Dixon-Salazar et al., 2004; Ferland et al., 2004) are associated mainly with symptoms restricted to the central nervous system. Several exceptions were reported where patients who carried mutations in AHI1 showed in addition a retinal phenotype that could range from RP to LCA (Valente et al., 2006). Although the function of the AHI1 protein is not known, the presence of a putative Src homology 3

(SH3) domain and six WD40 repeats suggests that AHI1 mediates the formation of

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large multi-protein complexes. Furthermore, the AHI1 protein may play also a role in common disorders that affect cognition and behavior since sequence variants of

AHI1 were found to associate with autism (Alvarez Retuerto et al., 2008). Deletion mutations in another gene, NPHP1, also known as JBTS4, have been found in few patients with Joubert syndrome (Valente et al., 2006) and Senior-Loken syndrome

(SLSN), a recessive form of RP (Caridi et al., 1998), although most mutations are responsible for isolated juvenile nephronophthisis. SLSN will be described elsewhere in this review. The gene product of NPHP1 is nephrocystin-1 and with the help of mouse models its role in intraflagellar transport could be demonstrated (Jiang et al.,

2009). Another component of the ciliary complex is a putative 2480-residue centrosomal protein encoded by CEP290. Mutations in this gene were associated with several aspects of Joubert syndrome, including those of retina and kidney

(Brancati et al., 2007; Valente et al., 2006). The severity of the ocular phenotype in these patients is similar to that characteristic of the Senior-Loken syndrome. It is noteworthy that mutations in CEP290 have been shown to be the most frequent cause of isolated LCA, in the absence of any renal or neurological involvement (den

Hollander et al., 2006; Perrault et al., 2007). Interestingly, one Joubert patient with a homozygous deletion affecting exon 36 of CEP290 showed the LCA ocular phenotype and complete situs inversus, suggesting a strong overlap between

Joubert syndrome and other ciliopathies (Brancati et al., 2007). This overlap is further supported by association of mutations in the gene CC2D2A with Joubert syndrome, including retinal defects. The CC2D2A product interacts in vitro with the

CEP290 protein (Gorden et al., 2008) and both proteins localize to the basal body.

Mutations in the gene ARL13B, encoding a further ciliary protein, ADP-ribosylation factor-like protein13B, can also lead to Joubert syndrome (Cantagrel et al., 2008).

ARL13B’s involvement in the retinal defect in Joubert syndrome has not been

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completely understood since only one Joubert syndrome patient displayed evidence of mild pigmentary retinopathy but normal ERG. Finally, the gene RPGR-interacting protein 1-like (RPGRIP1L), encoding a ciliary protein with specificity for the cilium of photoreceptors, is mutated in patients with CORS; among them also one patient with retinitis pigmentosa (Delous et al., 2007). Further screening did not yield additional individuals with retinitis pigmentosa, making it likely that mutations in this gene are largely confined to the cerebro-renal subgroup of Joubert syndrome (Brancati et al.,

2008). Frameshift mutations in the gene OFD1, which is known for its association with oral-facial-digital syndrome type 1, were recently found in a family segregating

X-linked Joubert syndrome with RP (Coene et al., 2009). As the previous examples showed, OFD1 also interacts with a component of the ciliary protein complex.

Depending on the dominant or recessive phenotype, interaction with LCA5 encoded ciliary protein lebercillin either abolishes or reduces binding (Coene et al., 2009).

These examples demonstrate the necessity of a functional ciliary complex and intraflagellar transport for normal retinal function. The findings also emphasize the genotypic-phenotypic complexity of the syndromic diseases with retinal involvement as stated elsewhere through out this review. Most recently, mutations in the gene

TMEM216, coding for a short protein of 87 amino acids predicted to form two transmembrane domains, were associated with Joubert syndrome type 2 (Edvardson et al., 2010). It is speculated, that it is part of the primary cilium, similar to TMEM67, which is also involved in Joubert syndrome (Baala et al., 2007; Dawe et al., 2007).

3.6 Alagille syndrome (ALGS)

Mutations in jagged 1 (JAG1) and the notch 2 receptor cause Alagille syndrome

(ALGS1 and ALGS2, Figure 4, Table 5)(McDaniell et al., 2006; Oda et al., 1997). The majority of cases can be explained by sequence alterations in JAG1. JAG1 is a

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transmembrane protein that constitutes a ligand in the notch pathway. Since the notch signalling is an important developmental pathway, relevant for several tissues

(reviewed by (Kopan et al., 2009), it is not surprising that ALGS1 includes a wide range of clinical manifestations (hepatic, cardiac, vascular, skeletal, ocular, facial, renal, pancreatic, and neuronal) (Piccoli et al., 2001). Clear genotype-phenotype correlations have not been observed in ALGS. Moreover, the phenotypes are highly variable among patients with JAG1 mutations (Colliton et al., 2001). Ocular features of ALGS may include optic disc drusen, angulated retinal vessels, a pigmentary retinopathy, and posterior embryotoxon (Kim et al., 2007). The disease is rare and affects approximately 1 in 100000 individuals. The mutations are inherited in an autosomal dominant pattern with reduced penetrance. Interestingly, the majority of the JAG1 mutations are nonsense mutations or small deletions leading to premature termination codons. Furthermore, some deletions affect the entire coding region of

JAG1. This supports the hypothesis that a reduced gene dosage (haploinsufficiency) may be the basis of the disease (Spinner et al., 2001).

3.7 Alstrom syndrome (ALMS)

Alstrom syndrome is a rare (less than 200000 affected individuals in US population) autosomal recessive disorder characterized by a progressive cone-rod photoreceptor dystrophy, sensorineural hearing loss, obesity and type II diabetis. In many patients cardiomyopathy, urological dysfunction and pulmonary, hepatic and renal failure develop as well. Despite its similarities to Bardet-Biedl syndrome, mental retardation, polydactyly and hypergonadism do not belong to the repertoire of features in Alstrom syndrome. Disruption of the gene ALMS1 (Figure 3, Table 3), located on chromosome 2, was found to associate with the syndrome (Collin et al., 2002; Hearn

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et al., 2002). The gene does not share identifiable homologies to other known genes or proteins and the proteins´ function is unknown (Marshall et al., 2007). ALMS1 is widely expressed and the protein subcellularly localizes to centrosomes and basal bodies of ciliated cells (Collin et al., 2002; Hearn et al., 2002). Among the identified mutations are nonsense and frame shift variations that are predicted to result in prematurely terminated proteins (Marshall et al., 2007). Exon 16 appears to contain a mutation hotspot as evidenced by the fact that 12% of all mutant alleles carry the deletion c.10775delC (Marshall et al., 2007). Patients with mutations in exon 16 also seem to express a more severe phenotype (Marshall et al., 2007). Phenotype- genotype correlations were suggestive between alterations in exon 16 and the retinal degeneration feature, if it manifested before the age of one year (Marshall et al.,

2007). Alm1 knockout mice aided in an attempt to understand the function of ALMS1.

With respect to the retinal phenotype, reduced b-wave responses in the ERG were observed that were followed by photoreceptor degeneration. Accumulation of intracellular vesicles in the inner segments and mislocalization of rhodopsin to the outer nuclear layer indicate that ALMS1 may play a role in intracellular trafficking

(Collin et al., 2005). As the morphological appearance of the cilia was not altered (Li et al., 2007) it seems likely that a functional rather than structural effect may be responsible for the phenotype.

3.8 Neuronal ceroid lipofuscinosis (NCLs or CLNs)

Neuronal ceroid lipofuscinosis are neurodegenerative lysosomal storage diseases.

They are characterized by the accumulation of autofluorescent material in different cell types including neurons. Clinical manifestations comprise epileptic seizures, progressive psychomotor retardation, visual loss, and premature death. Mutations occur in at least eight different genes (Figure 4, Table 5). The mode of inheritance is

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autosomal recessive. The age of onset is variable and defines, together with clinical manifestations, five different forms of NCLs (Kousi et al., 2009): 1. congenital form

(CLN10), 2. infantile form (INCL, CLN1), 3. late infantile form (LINCL, CLN2), 4. juvenile form (JNCL, CLN3), and 5. the adult form (ANCL, CLN4). Some of these forms are genetically heterogeneous in terms of genes where mutations have been described which lead to the clinical symptoms.

The infantile and late infantile forms are caused by mutations in the genes encoding the lysosomal enzymes palmitoyl-protein thioesterase 1 (PPT1) and tripeptidyl peptidase (TPP1), respectively (Sleat et al., 1997; Vesa et al., 1995). Mutations in the gene coding for cathepsin D, a lysosomal proteinase, were found in patients with congenital as well as later-onset NCLs (Fritchie et al., 2009; Siintola et al., 2006;

Steinfeld et al., 2006). Other NCL-associated genes encode lysosomal or endoplasmic reticulum proteins. CLN3 seems to be a lysosomal membrane protein

(International Batten Disease Consortium, 1995; Jarvela et al., 1998). CLN5 is expressed in cerebellar Purkinje cells, cerebral neurons, hippocampal pyramidal cells, and hippocampal interneurons. Thus, the expression pattern correlates with degenerated brain regions in CLN5 patients. Cell culture experiments revealed that

CLN5 is a soluble lysosomal glycoprotein (Holmberg et al., 2004; Isosomppi et al.,

2002). The CLN6 protein localized to the membranes of the endoplasmic reticulum

(Gao et al., 2002; Heine et al., 2004; Mole et al., 2004). The CLN7 gene codes for the lysosomal transporter MFSD8 (Siintola et al., 2007) and CLN8 for a membrane protein that localizes to the ER and ER-Golgi intermediate structure (Lonka et al.,

2000; Ranta et al., 1999).

3.9 Primary ciliary dyskinesia (PCD)

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PCD is a rare, autosomal recessive disease with a defect in ciliary function.

Progressive sinopulmonary disease is one of the cardinal features and approximately half of the patients have situs inversus (mirror orientation of thoraco-abdominal organs). Also male infertility is common and complex congenital heart disease can occur (Leigh et al., 2009a; Leigh et al., 2009b). The combination of situs inversus totalis, chronic sinusitis and bronchiectasis is also known as the Kartagener triad.

Almost all men with PCD are infertile from sperm immotility. Additional symptoms or clinical manifestations may include hydrocephalus, retinitis pigmentosa, polycystic kidney disease, liver cysts, biliary artresia. All those features are rare in PCD. Six genes are known to be mutated in PCD disease (Figure 2, Table 8) (Bartoloni et al.,

2002; Failly et al., 2008; Guichard et al., 2001; Ibanez-Tallon et al., 2002; Loges et al.,

2008; Omran et al., 2008; Pennarun et al., 1999; Schwabe et al., 2008). In addition to these genes an RPGR mutation was reported that leads to a combination of RP and

PCD (Moore et al., 2006). Mutations in DNAI1 and DNAH5 are responsible for about half of the cases, while mutations in the other genes are rare (Escudier et al., 2009).

3.10 Stickler syndrome

Among the vitreoretinopathies Stickler syndrome may be the most frequent one and unlike the others, it shows syndromic characteristics. The pattern of inheritance is autosomal dominant, with one published exception (Van Camp et al., 2006). The syndrome is a connective tissue disorder that can include eye, ear, joints and facial features (www.genereviews.org). Hearing problems can be conductive and sensorineural. Craniofacial features may include midface hypoplasia, depressed nasal bridge, anteverted nares, micrognathia, cleft palate and glossoptosis. The joint problems display hypermobility, mild spondyloepiphyseal dysplasia and also precautious osteoarthritis. Here we will focus on the ocular features which include

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myopia, cataract, vitreous anomalies and retinal detachment (also known as rhegmatogenous retinal detachment or RRD). The symptoms vary widely within and among Stickler families and individuals (Donoso et al., 2003) and some overlapping features with respect to the vitreous and retinal detachment have been observed with

Marshall syndrome (OMIM 154780). Based on the genetic cause and the pattern of inheritance different types of Stickler syndrome can be distinguished (Figure 5, Table

6). Collagen plays an important role in the disease pathology of all types as has become clear from mutation analyses. The autosomal recessive form involves the

COL9A1 gene (Van Camp et al., 2006) while the autosomal dominant form is caused by mutations in COL2A1, COL11A1 and COL11A2, all encoding different types of collagen (type II and type XI) constituting major components of the structural entities of cartilage and the vitreous. Mutations in the latter gene do not seem to affect the vitreous (Sirko-Osadsa et al., 1998). Additional Stickler loci are expected as not all families could be identified with mutations (Richards et al., 2002). A potential candidate is the gene encoding the nuclear protein TIA-1, which regulates alternative splicing of COL2A1 (McAlinden et al., 2007).

Mutations in COL2A1 comprise the majority of the genetic causes of Stickler syndrome. In a tissue-specific event, COL2A1 transcripts undergo alternative splicing such that exon 2 containing transcripts are found in the vitreous and those lacking exon 2 in cartilage. While mutations anywhere in the gene might give rise to both, systemic and ocular manifestation, one might expect that mutations in or near exon 2 would cause only ocular features. Clinical heterogeneity can only to some extent be correlated with mutations in exon 2 (Donoso et al., 2003; McAlinden et al.,

2008), which is supported by the finding that the ocular phenotype is predominantly caused by premature termination codon (PTC) mutations in exon 2. The same effect on splicing but via a different mechanism causes the c.170G

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substitution, which lies within a cis regulatory region involved in splicing of the mature transcript (McAlinden et al., 2008). Interestingly, a change of the same amino acid to a stop codon (p.Cys57Stop) was associated with Wagner syndrome (Gupta et al.,

2002). Since the two diseases share many similarities, the diagnosis may have been ambiguous (Richards et al., 2005). Taken together, differential splicing seems to be an important molecular mechanism for tissue-specific diseases, as has been observed for other syndromic diseases with ocular involvement and were discussed under RP. Although haploinsufficiency is the proposed disease mechanism for

Stickler syndrome, missplicing leads frequently to a dominant-negative effect with a more severe phenotype (Richards et al., 2005).

Mutations in COL11A1 are predicted to disrupt or alter collagen type XI. Among them are few deletion and insertion mutations but the majority of mutations affect splice sites at different intron-exon boundaries (Majava et al., 2007). We interpret that the effect of these mutations is comparable to those described above for COL2A1.

The question whether different, yet often overlapping features of disease conditions, are due to allelic states of a given gene can be answered by mutation analysis.

Using this approach, Marshall syndrome, which includes vitreous and retinal abnormalities, can be considered allelic to Stickler syndrome since mutations in

COL11A1 cause both (Majava et al., 2007).

4. Genetic testing and counselling

In order to diagnose and counsel patients and their families, knowledge about their disease-causing mutation is essential. Especially for genetic counseling, targeted clinical characterization and gene therapeutic interventions, the precise molecular diagnosis is very important. Unfortunately, the disease-causing mutation is often

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

difficult to identify due to the genetic heterogeneity and clinical variability of retinal diseases.

Several strategies do exist and novel technologies are emerging that increase the chance to identify the causative mutation in patients. For this purpose, knowledge of the pedigree is of utmost importance. It often provides significant clues to the selection of genes implicated for molecular genetic testing. In cases of autosomal dominant RP, the likelihood to identify the causative mutation among the five most frequently affected genes is approximately 50%. These five genes are rhodopsin

(RHO), peripherin 2 (PRPH2), retinitis pigmentosa 1 (RP1), pre-mRNA processing factor 31 (PRPF31), and inosine monophosphate dehydrogenase 1 (IMPDH1). The best candidate for adRP is rhodopsin, which accounts for up to 30% of the cases

(Kennan et al., 2005), whereas the other candidates have frequencies between 5 and

20%. Moreover, these five adRP genes comprise a total of only 40 coding exons, a number that seems manageable to be analyzed by conventional sequencing or other appropriate methods. Nevertheless, in cases of incomplete penetrance (carriers of the mutation are occasionally not affected), the collection of candidate genes is much smaller. Only three of the 19 adRP genes have been associated with incomplete penetrance (PRPF31, PAP1, and RP1). To optimize mutational screening procedures for such cases, a detailed case history including a family pedigree over several generations is needed to recognize incomplete penetrance of the phenotype.

In cases where the pedigree suggests X-linked inheritance within the family, RPGR and RP2 are the only candidates associated with RP so far. In addition, almost all cases can be explained by mutations in either RPGR (up to 80% of the cases) or

RP2 (up to 20% of the cases) (Neidhardt et al., 2008; Roepman et al., 1996b;

Schwahn et al., 1998). A screening strategy starting with a mutation hot spot in

RPGR followed by sequencing of other exons has been shown to be successful in

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

most cases and to reduce costs and efforts (Neidhardt et al., 2008). Additional loci on the X-chromosome have been mapped, but the corresponding genes have not yet been identified. Interestingly, RPGR mutations may also affect female carriers and thus should not be associated with classical X-linked recessive inheritance. The genetic basis for this observation is still unclear. Since skewed X-inactivation has not been identified in affected female carriers so far, genetic or environmental modifiers may be relevant too. In contrast to X-linked RP, the candidate selection is more difficult in cases with autosomal recessive inheritance. Promising candidate genes for arRP are PDE6alpha and PDE6beta that together explain about 5-10% of the cases

(Daiger et al., 2007). USH2A is a gene frequently found to be mutated in arRP (up to

20% of the cases), but is also associated with Usher Syndrome ((Hartong et al., 2006) and references therein). Furthermore, ABCA4 and RPE65 often show RP-associated mutations, but classically cause Stargardts disease or LCA (Figures 2, 3, 4 and 6,

Tables 2, 3 and 5). Thus, a thorough clinical characterization of the phenotype including syndromic features will further facilitate the selection of candidate genes for molecular genetic testing in a patient with arRP.

Following these screening strategies, the samples without identified mutations may be included in research programs to identify novel loci and disease-associated genes.

Methods that are used to further characterize such samples often include array technologies (SNP arrays) with the aim to identify linkage intervals in families with multiple affected members or homozygous regions in the genome of consanguineous families. Furthermore, array technologies may be used to directly screen for mutations (Koenekoop et al., 2007).

In particular, genetic testing for the large gene ABCA4 and for all recessive or dominant RP genes requires efficient diagnostic tests in order to examine the DNA sample of a patient in an affordable amount of time. One such tool for mutation

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detection represent microarrays. This technique has been established for several retinal diseases (Cremers et al., 2007; Jaakson et al., 2003; Zernant et al., 2005).

Also for CSNB, the large number of genes and mutations associated with this disease are challenging for confirmation of the clinical diagnosis. Recently, a microarray has been developed which provides a fast and rather inexpensive tool to screen DNA samples from patients for known mutations in one of the above mentioned genes (Zeitz et al., 2009). However, with this diagnostic test only known sequence alterations can be detected as in the case of ABCA4 (Klevering et al.,

2004b). The most sensitive technology currently available for routine diagnostics is direct DNA sequencing in combination with multiple ligation-dependent probe amplification (MLPA), the latter of which can be used to reveal copy number variations, such as deletions or duplications.

Another challenge for genetic testing is the interpretation of the results of these tests.

Many of the DNA sequence variations lead to amino acid substitutions and it is difficult to predict the pathogenic effect for many of them. Therefore, functional assays are needed to characterize these sequence alterations. For example, ABCA4 possesses an ATPase activity and it is possible to analyze specific missense mutations in cell culture assays and answer the question of a potential pathogenic effect (Sun et al., 2000). Due to the extensive individuality of pathogenic and non- pathogenic sequence alterations, this approach is difficult to realize in a routine diagnostic setting. In addition, deep intronic mutations may be responsible for a significant number of cases and these are extremely difficult to be analyzed in functional assays.

Today, the new (next generation) sequencing technologies enable us to collect up to

500 million base pairs per single sequencing run at comparably low costs

(Voelkerding et al., 2009). This will complement or even replace other methods to

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identify mutations in genetically heterogeneous diseases, such as retinal degenerations and dysfunctions.

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5. Therapeutic approaches to retinal degenerations

The eye is ideally suited as a target organ for several different therapeutic approaches as it is easy to access and enables to monitor the application of therapeutics. It further allows a non-invasive follow up of therapeutic effects in vivo.

Its interconnected system of spatially well organized cell types facilitates the application of therapeutics to the target cells. Moreover, the eye shows an efficient blood-retinal barrier that greatly reduces or even prevents exchange of therapeutics with other organs and thus may limit side effects and further therapy-provoked immune responses like inflammation. In contrast to non-syndromic retinal diseases, it will be difficult to treat extraocular symptoms in patients with a syndromic form of retinal degeneration, e.g. Refsum disease, Joubert syndrome, Bardet Biedl syndrome, or others.

Different avenues are currently followed in order to treat patients with retinal diseases.

These include the application of nutrition supplements or drugs, gene replacement strategies, transplantation and stem cell technologies, as well as the implantation of electric devices, known as retinal prosthesis.

We will discuss two therapeutic approaches that have advanced from successful application in animal models to phase 1 and/or 2 clinical trials: One strategy involves neurotrophic and survival factors that have been shown, for example in animal models, to prolong the lifespan of affected retinal cells. The other one uses gene replacement. Both showed a significant success rate for several inherited retinal diseases.

The ciliary neurotrophic factor (CNTF) yielded promising results in two phase 2 studies. The therapeutic intervention, designated ´Encapsulated Cell Technology

(ECT, (Lanza et al., 1996))´, involves intraocular implants containing human cells, which secrete CNTF (Emerich et al., 2008; Thanos et al., 2004). A therapeutic device,

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designated NT-501, was developed recently. Treatment of more than 120 patients with RP revealed a positive biological effect in the retina and photoreceptors, as measured by optical coherence tomography (OCT). However, the patients have been monitored only for a relatively short period of time (12 months). Preliminary results of these trials are encouraging but a long term follow-up is needed to evaluate the success of treatment and possible adverse effects. A positive effect measured by

OCT has also been observed in patients with the dry form of AMD and geographic atrophy who were treated with NT-501 implants. The wet form of AMD may also be treated by delivering a structural antagonist of VEGF to the affected eye. Possible application of encapsulated cell technology (ECT) in AMD treatment was recently initiated (NT-503).

In therapeutic approaches that apply gene replacement technologies, viral vectors have frequently been used to transduce retinal cells with intact copies of the mutated gene. In most cases, either the recombinant adeno-associated virus (rAAV) or the lentivirus provided the basis for the viral shuttle. Since cell specificity, expression kinetics and packaging size differ significantly between these viruses, the selection of the optimal virus type is essential for the therapeutic outcome. Furthermore, combinations of different rAAV serotypes enable an even more controlled use of cell specificity and expression kinetics (Auricchio et al., 2005; Neidhardt et al., 2005). For example, the serotype rAAV2/4 is more specific to RPE than rAAV2/5, which additionally transduces photoreceptors (Acland et al., 2005; Weber et al., 2003).

Their expression kinetics are similarly fast, while rAAV2/2-mediated expression is significantly slower. An advantage of the lentivirus is to host larger genes of interest than rAAV. It is specific to RPE cells after subretinal delivery (Tschernutter et al.,

2005).

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LCA patients with RPE65 mutations were the first to be treated successfully by gene replacement therapies in three independent phase 1 clinical trials (Bainbridge et al.,

2008; Hauswirth et al., 2008; Maguire et al., 2008). These clinical trials have been stimulated by encouraging results in a naturally occurring dog model of RPE65 mutations (Acland et al., 2001). It further seemed a promising target gene for replacement therapy since the RPE65 deficiency results in visual impairment due to depletion of visual pigment from the phototransduction cascade, but shows a high degree of preservation of anatomical features within the retina. Furthermore, RPE65 is RPE specific and subretinal injection of viral shuttles can more efficiently transduce

RPE than photoreceptor cells, possibly because of anatomical barriers. Together with the appropriate choice of rAAV serotypes for the transduction of RPE cells, the gene therapy of RPE65 mutations resulted in increased retinal sensitivity in young adult patients (Bainbridge et al., 2008; Hauswirth et al., 2008; Maguire et al., 2008). Some patients had improved visual abilities in dim light conditions although the effect was not detectable by ERG measurements. Importantly, significant side effects of the viral treatment have not been detected so far. Future evaluations of long-term effects will be needed to judge safety aspects and therapeutic potential of this first gene replacement therapy in the eye.

In general, gene replacement is more feasible in patients with loss of function mutations, represented by either recessive or dominant haploinsufficient alleles. In contrast, dominant negative mutations require two steps of therapeutic intervention: (i) inactivation or depletion of the dominant negative gene variant or gene product and

(ii) introduction and expression of the healthy gene copy. This two-step approach is more challenging but several strategies to accomplish this are available (Millington-

Ward et al., 1997). In addition, the discovery of RNA interference mechanism may provide a suitable tool for the specific removal of transcripts encoding dominant

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negative protein species of a given gene. The development of current gene replacement therapies focusses on genes that are frequently affected by recessive mutations, including PDE, ABCA4, CNGB3, GNAT2, and AIPL1.

Future candidate genes for clinical trials will be selected on the basis of successful treatment of an appropriate animal model, the frequency of the mutations found within the respective gene, and the significance of the benefit expected for the patient.

Furthermore, it is well possible that existing therapies will be improved by gene therapy approaches. The treatment of AMD often requires repeated injection of rather expensive medications over years. Gene therapy could lead to a permanent presence of AMD therapeutic agents in the eye, thus substituting repeated injections.

Moreover, one might speculate that drug-inducible expression systems will be applied to control expression of the therapeutic protein in the eye. Such systems would also be beneficiary to enable the adjustment of therapeutic concentrations towards inter-individual phenotype differences.

In summary, gene therapy and the application of substances that prolong the lifespan of affected retinal cells offer a multitude of possibilities that will contribute to the treatment of retinal diseases and will help to slow down or even stop the progression of several blinding eye diseases in the near future. For some of them, knowledge of the disease causing mutation will be essential prior to a specific application. But for others, a more general therapeutic approach, like treatment with neurotrophic or antiapoptotic factors, will be possible without knowing the pathogenic gene variant.

However, we do not yet know or understand how a specific genotype contributes to the therapeutic outcome. Therefore, genotyping of patients and a detailed comparison of the genotype with the course of the therapeutic intervention will provide important informations with regard to a combinatorial effect of DNA variants, environmental factors, and the procedure of treatment.

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6. Conclusions and outlook

The future in the field of retinal diseases will focus on the identification of additional genes, the development of efficient and reliable diagnostic tests, and most importantly on the development of treatment regimens.

Disease gene identification has become much more efficient with the availability of the human genome sequence. What it needs today are comprehensive databases integrating genetic but also clinical data in order to perform a detailed genotype- phenotype comparison. This can reveal important information not only to diagnose a disease in a patient or family for genetic counselling, but it may also have a predictive value with respect to the likelihood of disease development and choices of therapy.

The recent progress in sequencing technology, including next and third generation sequencing, will provide sequence information of entire introns in addition to exons. It will further be feasible to sequence a complete set of genes with important functions in retina, RPE, vitreous, but also other ocular structures. This will lead to the identification of numerous DNA variations. The challenge is to discriminate between the causative mutations, modifying alleles or other sequence variants, which confer a risk or protection for the development of an ocular disease. To evaluate all these variants, bioinformatic tools as well as sequence variation databases and clinical data from patients are extremely important for the interpretation of the sequencing results.

Current development of treatments is very encouraging and will improve the quality of life of a patient. Nevertheless, years if not decades of work is ahead of us, which will deliver important and exciting results in basic research and therapy.

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Internet Resources:

ENSEMBL: http://www.ensembl.org/index.html GeneReviews: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests GeneTests: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests MedMolGen: http://www.medmolgen.uzh.ch/index.html NCBI: http://www.ncbi.nlm.nih.gov/ OMIM: http://www.ncbi.nlm.nih.gov/omim/ Pubmed: http://www.ncbi.nlm.nih.gov/pubmed/ Retnet: http://www.sph.uth.tmc.edu/retnet/ UCSC: http://genome.ucsc.edu/

Acknowledgements:

We would like to acknowledge the work of a large community of medical and basic researchers, clinicians, counsellors and other professionals, who contributed so much and significantly to the field. Special thanks go to the patients as well as their families and we hope that they, or their children, may become the beneficiaries. We also acknowledge our coworkers in the Division of Medical Molecular Genetics and

Gene Diagnostics (University of Zurich Medical School) and our external collaborators for their stimulating, enthusiastic and motivated input to our research.

We appreciate support from the funding agencies and patient organizations. Finally, we would be gratefull to all the readers who are willing to share with us their thoughts about the different aspects of this review article.

If we have missed to cite any relevant contributions from our colleagues in the field, we sincerely apologize.

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

Figure Legends:

Figure 1

Classification of monogenic familial retinal and vitreoretinal diseases. The disorders are categorized according to the photoreceptor cell type or ocular structure which are affected by the disease. Rod as well as cone dominated diseases are subdivided in stationary (yellow) and progressive (red) forms. Generalized photoreceptor diseases and vitreoretinal diseases are predominantly progressive. The progressive forms are non-syndromic or part of a multiorgan disease (syndromic). The + signs indicate that detailed informations and further subclassifications are available in Figures 2 to 5.

Figure 2

Rod over cone photoreceptor diseases. The diseases are either stationary or progressive. Disease-causing mutations in different genes are dominant, recessive, or X-linked. In syndromic forms, RP occurs together with disease symptoms in non- ocular tissues or organs. The respective genes are indicated by gene symbols.

Figure 3

Cone over rod photoreceptor diseases. The stationary forms affect color vision. The progressive cone diseases can be subdivided in cone and cone rod dystrophies as well as macular degenerations. Both occur syndromic or non-syndromic. The different genes involved in these diseases are indicated by gene symbols. Mutations are dominant, recessive, or X-linked.

Figure 4

Generalized photoreceptor diseases affect both photoreceptor cell types, rods and cones. They are progressive in the majority of cases and can occur as part of a

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) The molecular basis of human retinal and vitreoretinal diseases

syndrome (syndromic) or not (non-syndromic). Mutations in various genes, indicated by their symbols, are dominant or recessive. X-linked inheritance has not been described so far.

Figure 5

Exudative and erosive vitreoretinopathies (ERVR and EVR). Both, syndromic and non-syndromic forms can be caused by dominant, recessive, or X-linked mutations in different genes (indicated by gene symbols).

Figure 6

Clinical symptoms of non-syndromic monogenic retinal and vitreoretinal diseases and their causative genes. Clinical diagnoses are indicated by colored circles. Gene symbols in the overlapping areas show that mutations in the same gene can lead to different phenotypes.

RP: retinitis pigmentosa; NB: night blindness; LCA: Leber congenital amaurosis;

CORD/COD: cone-rod and cone dystrophies; CVD: color vision defects; MD: macular degeneration; ERVR/EVR: erosive and exudative vitreoretinopathies

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Figure 1

Monogenic familial retinal and vitreoretinal diseases

Rod > cone photoreceptor diseases Cone > rod photoreceptor diseases Generalized photoreceptor diseases Vitreoretinopathies (exudative and erosive)

stationary progressive stationary progressive progressive progressive

non syndromic syndromic Cone & cone rod dystrophies (CODs & CORDs) Macular degenerations (MDs) non syndromic syndromic non syndromic syndromic

non syndromic syndromic non syndromic syndromic

Figure_1 (2).mmap - 22.12.2009 - Mindjet Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Figure 2

Rod > cone photoreceptor diseases

stationary progressive

dominant non syndromic syndromic

dominant recessive Night blindness: GNAT1, PDE6B, RHO Retinitis pigmentosa: Bardet Biedl syndrome: BEST1, CA4, CRX, BBS1, BBS2, BBS3, BBS4, FSCN2, GUCA1B, BBS5, BBS6, BBS7, BBS8, recessive IMPDH1, KLHL7, BBS9, BBS10, BBS11, NR2E3, NRL, PAP1, BBS12, CEP290 PRPF3, PRPF8, Incomplete night blindness: PRPF31, PRPH2, Joubert syndrome: CABP4, (CACNA2D4) RDH12, RGR, RHO, AHL1, ARL13B, ROM1, RP1, SEMA4A, CC2D2A, CEP290, Complete night blindness: SNRNP200, TOPORS NPHP1, RPGRIP1L, GRM6, TRPM1 TMEM67, TMEM216 recessive Primary ciliary dyskinesia (PCD): Oguchi disease: DNAH5, DNAH11, DNAI1, SAG, GRK1 Retinitis pigmentosa: DNAI2, KTU, TXNDC3 ABCA4, BEST1, CERKL, Refsum disease: X-linked CNGA1, CNGB1, CRB1, EYS, LRAT, MERTK, PAHX, PEX1, PEX7, NR2E3, NRL, PDE6A, PEX26, PXMP3 PDE6B, PRCD, PROM1, Incomplete night blindness: Senior Loken syndrome: RBP3, RGR, RHO, RLBP1, CACNA1F CEP290, NPHP1, NPHP2, RP1, RPE65, SAG, TULP1, NPHP3, NPHP4, NPHP5 Complete night blindness: USH2A NYX Usher syndrome: X-linked CLRN1, CLRN3, DFNB31, GPR98, MYO7A, PCDH15, Retinitis pigmentosa: SANS, USH1C, USH1D, RP2 (semi-dominant and USH2A recessive), RPGR (dominant and recessive) X-linked

Joubert syndrome: OFD1

Retinitis pigmentosa with deafness and sinorespiratory infections: RPGR

Figure_2.mmap - 16.02.2010 - Mindjet Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Figure 3

Cone > rod photoreceptor diseases

stationary progressive

dominant Cone & cone rod dystrophies (CODs & CORDs) Macular degenerations (MDs)

Tritanopia: BCP non syndromic syndromic non syndromic syndromic

recessive dominant dominant dominant dominant

AIPL1, CRX, Neurofibromatosis 1: NF1 BEST1, C1QTNF5, Spinocerebellar ataxia (SCA): Complete achromatopsia: GUCA1A, GUCY2D, CNGB3, EFEMP1, SCA7/ATXN7 CNGA3, CNGB3, GNAT2, HRG4/UNC119, Spinocerebellar ataxia 7: ELOVL4, HMCN1, PDE6C PITPNM3, PROM1, SCA7 (ATXN7) FSCN2, GUCA1B, recessive PRPH2, RAX2, RIM1, PROM1, PRPH2, SEMA4A TIMP3 Incomplete achromatopsia: recessive CNGA3, GNAT2, PDE6C Bardet Biedl syndrome : BBS1 recessive recessive Alström syndrome: ALMS1 Hypotrichosis with Oligocone trichromacy: juvenile MD: CDH3 CNGB3, GNAT2 ABCA4, ADAM9, Bardet Biedl syndrome : BBS1 ABCA4 CACNA2D4, CNGA3, Infantile Refsum disease: KCNV2, PDE6C, PDE6H, CORD with PEX1, PEX26, PXMP3 X-linked X-linked RDH5, RLBP1, amelogenesis RPGRIP1, SEMA4A imperfecta: CNNM4 RPGR, RS1 Blue cone monochromatism: X-linked GCP, RCP

CACNA1F, RPGR

Figure_3.mmap - 26.02.2010 - Mindjet Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Figure 4

Generalized photoreceptor diseases

progressive

non syndromic syndromic

dominant dominant

Leber congenital amaurosis: Alagille syndrome: CRX, IMPDH1 JAG1, NOTCH2

recessive recessive

Leber congenital amaurosis: Neuronal ceroid lipofuscinosis: AIPL1, CEP290, CRB1, CRX, BTS, CLN5, CLN6, CLN7, CLN8, GUCY2D, IMPDH1, LCA5, CTSD, PPT1, TPP1 LRAT, MERTK, RD3, RDH12, RPE65, RPGRIP1, SPATA7, Refsum disease: TULP1 PAHX, PEX1, PEX7, PEX26, PXMP3 Gyrate atrophy: OAT Joubert syndrome: AHL1, ARL13B, X-linked CC2D2A, CEP290, NPHP1, RPGRIP1L, Choroideremia: CHM TMEM67, TMEM216 Senior Loken syndrome: CEP290

Figure_4.mmap - 26.02.2010 - Mindjet Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Figure 5

Vitreoretinopathies (exudative and erosive)

progressive

non syndromic syndromic

dominant dominant

Exudative vitroretinopathy Stickler syndrome 1 (EVR): FZD4 (EVR1 ), (STL1): COL2A1 TSPAN12 Stickler syndrome 2 Wagner disease (STL2): COL11A1 (WGN1): VCAN Stickler syndrome 3 Snowflake vitreoretinal (STL3): COL11A2 degeneration: KCNJ13

Vitreoretinal choroidopathy: BEST1 recessive

recessive Osteoporosis pseudoglioma syndrome (OPPG): LRP5

Exudative vitroretinopathy 4 Stickler syndrome (STL): COL9A1 (EVR4): LRP5

Enhanced S-cone syndrome, Goldmann X-linked Favre syndrome (GFS): NR2E3 Norrie disease: NDP X-linked

Exudative vitroretinopathy 2 (EVR2): NDP

Figure_5.mmap - 15.02.2010 - Mindjet Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Figure 6

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 1: Stationary photoreceptor diseases Congenital stationary night blindness (CSNB) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional phenotypes Calcium-binding protein 4 CABP4 CSNB2B 11q13.1 recessive NM_145200 calcium signalling incomplete CSNB, progressive Voltage-dependent L-type calcium channel subunit CACNA1F CSNB2A, CORDX3, Xp11.23 recessive NM_005183 Calcium channel incomplete congenital stationary night blindness alpha-1F Cav1.4, CSNB2A, CSNBX2 Calcium channel, voltage-dependent, alpha 2/delta CACNA2D4 RCD4 12p13.33 recessive NM_172364 ion channel incomplete CSNB, cone dystrophy (ar) subunit 4 Guanine nucleotide-binding protein G(t) subunit GNAT1 - 3p21.31 dominant NM_144499 phototransduction - alpha-1 Rhodopsin kinase GRK1 GPRK1, RHOK, RK 13q34 recessive NM_002929 phototransduction CSNB with fundus abnormalities Metabotropic glutamate receptor 6 GRM6 CSNB1B, MGLUR6, 5q35 recessive NM_000843 glutamate transport complete CSNB GPRC1F Nyctalopin NYX CSNB1A Xp11.4 recessive NM_022567 unknown complete CSNB Rod cGMP-specific 3',5'-cyclic phosphodiesterase PDE6B PDEB, CSNB3, RP40 4p16.13 dominant NM_001145292 phototransduction retinitis pigmentosa subunit beta Rhodopsin RHO OPN2, RP4 3q22.1 dominant NM_000539 phototransduction retinitis pigmentosa Transient receptor potential cation channel subfamily TRPM1 LTRPC1, MLSN1 15q13.3 recessive NM_002420 ion channel complete CSNB M member 1 S-arrestin SAG Arrestin 2q37.1 recessive NM_000541 phototransduction CSNB with fundus abnormalities

Cone dysfunctions (stationary) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional phenotypes Cyclic nucleotide-gated channel alpha-3 subunit CNGA3 ACHM2, CNCG3, 2q11.2 recessive NM_001298 phototransduction complete or incomplete achromatopsia, typical or CCNCa, CNG3, atypical achromatopsia, rod monochromatism, cone CCNC1 rod dystrophy (ar) Cyclic nucleotide-gated cation channel beta-3 CNGB3 ACHM3 8q21.3 recessive NM_019098 phototransduction complete achromatopsia, typical achromatopsia, rod subunit monochromatism, macular degeneration Guanine nucleotide-binding protein G(t) subunit GNAT2 ACHM4 1p13.3 recessive NM_005272 phototransduction complete or incomplete achromatopsia, typical or alpha-2 atypical achromatopsia, rod monochromatism, oligocone trichromacy Cone-specific phosphodiesterase alpha subunit PDE6C PDEA2 10q23.33 recessive NM_006204 phototransduction complete or incomplete achromatopsia, cone dystrophy Red cone photoreceptor pigment RCP OPN1LW, CBBM, CBP Xq28 recessive NM_020061 phototransduction blue cone monochromatism, X-linked atypical achromatopsia, X-linked incomplete achromatopsia

Green cone photoreceptor pigment GCP OPN1MW, CBBM, Xq28 recessive NM_001048181 phototransduction blue cone monochromatism, X-linked atypical CBD, OPN1MW1 achromatopsia, X-linked incomplete achromatopsia

Blue cone photoreceptor pigment OPN1SW BCP, CBT 7q32.1 dominant NM_001708 phototransduction tritanopia

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information

Table_1.xls 12.03.2010 1 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 2: Retinitis pigmentosa (RP) Retinitis pigmentosa Gene names Gene symbol Gene symbol aliases Chromosome Inheritance Reference sequence Potential function Additional phenotype Carbonic anhydrase 4 CA4 RP17 17q23.2 dominant NM_000717 unknown - Cone-rod homeobox protein CRX CORD2, CRD, OTX3, 19q13.32 dominant NM_000554 transcription factor cone rod dystrophy (ad), Leber congenital LCA7 amaurosis (ar and ad) Fascin homolog 2 FSCN2 RP30 17q25.3 dominant NM_012418 cellular structure macular dystrophy (ad) Guanylate cyclase activator 1B GUCA1B GCAP2 6p21.1 dominant NM_002098 phototransduction macular dystrophy (ad) Inosine monophosphate dehydrogenase 1 IMPDH1 RP10, LCA11, MPD, 7q32.1 dominant NM_000883 regulation of cell growth Leber congenital amaurosis (ad) IMPD1, Kelch-like 7 KLHL7 RP42, SBBI26 7p15 dominant NM_001031710 ubiquitin-proteasome protein - degradation Pim1 associated protein 1 PAP1 RP9, PIM1K 7p14.3 dominant NM_203288 splicing - Pre-mRNA processing factor 3 homolog PRPF3 RP18, HPRP3, PRP3 1q21.2 dominant NM_004698 splicing - Pre-mRNA processing factor 31 homolog PRPF31 RP11, PRP31 19q13.42 dominant NM_015629 splicing - Pre-mRNA processing factor 8 homolog PRPF8 RP13, PRPC8 17p13.3 dominant NM_006445 splicing - Peripherin 2 PRPH2 RP7, RDS, TSPAN22, 6p21.1 dominant NM_000322 photoreceptor outer segment macular dystrophy (ad), digenetic forms with rd2 structure ROM1, adult vitelliform macular dystrophy (ad), pattern dystrophy

Retinol dehydrogenase 12 RDH12 LCA3, LCA13, SDR7C2, 14q24.1 dominant NM_152443 phototransduction Leber congenital amaurosis (ar) FLJ30273 Retinal outer segment membrane protein 1 ROM1 RP7, ROSP1, TSPAN23 11q12.3 dominant NM_000327 cellular structure digenic forms with PRPH2 sema domain, immunoglobulin domain (Ig), SEMA4A RP35, CORD10, SEMAB, 1q22 dominant NM_022367 tissue development and cone rod dystrophy (ad) transmembrane domain (TM) and short SemB maintenance cytoplasmic domain, (semaphorin) 4A Small nuclear ribonucleoprotein 200kDa (U5) SNRNP200 BRR2, HELIC2, 2q11.2 dominant NM_014014 splicing - ASCC3L1, U5-200KD Topoisomerase I binding, arginine/serine-rich TOPORS RP31, LUN, P53BP3 9p21.1 dominant NM_005802 - -

Bestrophin-1 BEST1 VMD2, ARB, BMD, 11q12.3 dominant and NM_004183 anion channel autosomal dominant TU15B, recessive vitreoretinochoroidopathy; Best macular dystrophy (BMD) (ad) Nuclear receptor subfamily 2, group E, NR2E3 ESCS, PNR, RP37, 15q22.32 dominant and NM_016346 transcription factor enhanced S-cone syndrome (ar), Goldmann- member 3 MGC49976, rd7, RNR recessive Favre syndrome Neural retina leucine zipper NRL RP27 14q11.2 dominant and NM_006177 tissue development and may include clumped pigmentary recessive maintenance degeneration and preserved blue cone function Retinal G protein coupled receptor RGR RP44 10q23.1 dominant and NM_002921 retinal metabolism choroidal sclerosis (ad) recessive Rhodopsin RHO RP4, OPN2 3q22.1 dominant and NM_000539 phototransduction CSNB (ad) recessive Retinitis pigmentosa 1 RP1 ORP1 8q12.1 dominant and NM_006269 tissue development and - recessive maintenance

Table_2.xls 12.03.2010 1 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) ATP-binding cassette, sub-family A member 4 ABCA4 RP19, ABCR, ARMD2, 1p22.1 recessive NM_000350 transport Stargardt disease, cone rod dystrophy, CORD3, STGD1 juvenile and late onset macular degeneration, fundus flavimaculatus; all (ar)

Ceramide kinase-like CERKL RP26 2q31.3 recessive NM_001030311 tissue development and - maintenance Cyclic nucleotide gated channel alpha 1 CNGA1 CNCG, CNCG1 4p12 recessive NM_000087 phototransduction - Cyclic nucleotide gated channel beta 1 CNGB1 CNCG2, CNCG3L, 16q13 recessive NM_001297 phototransduction - GAR1, GARP Crumbs homolog 1 CRB1 RP12, LCA8, RP11, 1q31.3 recessive NM_201253 tissue development and Leber congenital amaurosis (ar), pigmented maintenance paravenous chorioretinal atrophy (ad), retinitis pigmentosa (ar) with para-arteriolar preservation of the RPE, sympotoms may include Coats-like exudative vasculopathy and thick retina with abnormal lamination

Eyes shut homolog EYS RP25, SPAM 6p12 recessive NM_001142800 - - Lecithin retinol acyltransferase LRAT MGC33103 4q32.1 recessive NM_004744 retinal metabolism Leber congenital amaurosis (ar) C-mer proto-oncogene tyrosine kinase MERTK RP38, MER, c-mer 2q14.1 recessive NM_006343 transmembrane protein LCA Phosphodiesterase 6A PDE6A RP43, CGPR-A 5q33.1 recessive NM_000440 phototransduction - Phosphodiesterase 6B PDE6B RP40, CSNB3 4p16.3 recessive NM_000283 phototransduction CSNB (ad) Progressive rod-cone degeneration PRCD RP36 17q25.1 recessive NM_001077620 - - Prominin 1 PROM1 CORD12, CD133, RP41, 4p15.32 recessive NM_006017 cellular structure retinitis pigmentosa with macular STGD4, AC133, MCDR2, degeneration (ar); Stargardt-like macular PROML1 dystrophy (ad); macular dystrophy (ad); bull's- eye; cone rod dystrophy (ad)

Retinol binding protein 3 RBP3 IRBP 10q11.22 recessive NM_002900 retinal metabolism - Retinaldehyde binding protein 1 RLBP1 CRALBP 15q26.1 recessive NM_000326 retinal metabolism rod-cone dystrophy (ar), retinitis punctata albescens (ar), Newfoundland rod cone dystrophy (ar) Retinal pigment epithelium-specific protein RPE65 RP20, LCA2 1p31.2 recessive NM_000329 retinal metabolism Leber congenital amaurosis (ar) 65kDa Arrestin, s-antigen SAG RP47, DKFZp686D1084, 2q37.1 recessive NM_000541 phototransduction Oguchi disease (ar) DKFZp686I1383

Tubby like protein 1 TULP1 RP14, TUBL1 6p21.31 recessive NM_003322 tissue development and Leber congenital amaurosis (ar) maintenance Usher syndrome 2A USH2A RP39, USH2, 1q41 recessive NM_206933 cellular structure Usher syndrome, type 2a (ar) Retinitis pigmentosa 2 RP2 NME10, TBCCD2, Xp11.23 recessive NM_006915 tissue development and - KIAA0215, DELXp11.3 maintenance Retinitis pigmentosa GTPase regulator RPGR RP3, CORDX1, COD1, Xp11.4 recessive NM_000328 intraflagellar transport cone rod dystrophy (Xl), atrophic macular CRD, RP15 dystrophy (Xl), cone dystrophy (Xl)

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information

Table_2.xls 12.03.2010 2 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 3: Non-syndromic and syndromic cone and cone rod dystrophies Non-syndromic cone and cone rod dystrophies (COD, CORD, progressive) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Clinical diagnosis ATP-binding cassette sub-family A member 4 ABCA4 CORD3, FFM, STGD1, 1p22.1 recessive NM_000350 transport Stargardt disease, retinitis pigmentosa, cone rod RP19, ABCR, STGD, dystrophy, juvenile and late onset macular degeneration, ARMD2 fundus flavimaculatus; all (ar) Metalloprotease disintegrin cysteine-rich protein ADAM9 MDC9, MCMP 8p11.22 recessive NM_003816 cell/matrix interaction cone rod dystrophy 9 Aryl-hydrocarbon-interacting protein-like 1 AIPL1 LCA4, AIPL2 17p13.1 dominant NM_014336 transport, protein cone rod dystrophy, Leber congenital amaurosis (ar) trafficking Voltage-dependent L-type calcium channel CACNA1F CORDX3, CSNB2, Xp11.23 recessive NM_005183 Calcium channel congenital stationary night blindness, cone rod dystrophy subunit alpha-1F Cav1.4, CSNB2A, CSNBX2 Voltage-dependent calcium channel subunit CACNA2D4 RCD4 12p13.33 recessive NM_172364 ion channel cone dystrophy (ar), stationary night blindness (ar) alpha-2/delta-4 Cyclic nucleotide-gated cation channel beta-3 CNGA3 ACHM2, CNCG3, 2q11.2 recessive NM_001298 phototransduction complete or incomplete achromatopsia, typical or atypical subunit CCNCa, CNG3, CCNC1 achromatopsia, rod monochromatism, cone rod dystrophy (ar) Cellular retinaldehyde-binding protein CRALBP RLBP1 15q26.1 recessive NM_000326 phototransduction retinitis pigmentosa (ar), rod cone dystrophy (ar) Cone-rod homeobox protein CRX CORD2, CRD, OTX3, 19q13.32 dominant NM_000554 transcription factor cone rod dystrophy (ad), Leber congenital amaurosis (ad, LCA7 ar), retinitis pigmentosa (ad) Guanylate cyclase activator 1A GUCA1A GCAP1, GUCA, GCAP, 6p21.1 dominant NM_000409 phototransduction cone dystrophy (ad) Color and central vision loss (ad) GUCA1, COD3 Retinal guanylate cyclase 2D GUCY2D CORD6, GUC1A4, 17p13.1 dominant NM_000180 phototransduction Leber congenital amaurosis (ar) GUC2D, LCA1, LCA, retGC, CYGD, RETGC-1, ROS-GC1, CORD5

Protein unc-119 homolog A, retinal protein 4 HRG4 UNC119 17q11.2 dominant NM_005148 neurotransmitter release cone rod dystrophy (ad)

Potassium voltage-gated channel subfamily V KCNV2 Kv8.2, RCD3B 9p24.2 recessive NM_133497 ion channel subunit cone dystrophy with supernormal rod electroretinogram member 2 Cone -specific phosphodiesterase alpha subunit PDE6C PDEA2 10q23.33 recessive NM_006204 phototransduction complete or incomplete achromatopsia, cone dystrophy

Retinal cone rhodopsin-sensitive cGMP 3',5'- PDE6H RCD3A 12p12.3 recessive NM_006205 phototransduction cone dystrophy with supernormal rod electroretinogram cyclic phosphodiesterase subunit gamma Membrane-associated phosphatidylinositol PITPNM3 CORD5, NIR1, RDGBA3 17p13.2 dominant NM_031220 transport cone rod dystrophy transfer protein 3 Prominin 1 PROM1 CORD12, CD133, RP41, 4p15.32 dominant NM_006017 cellular structure Stargardt disease (ad), retinitis pigmentosa (ar), cone rod STGD4, AC133, MCDR2, dystrophy (ad), macular degeneration (ad) PROML1

Peripherin-2 PRPH2 RP7, RDS, TSPAN22, rd2 6p21.1 dominant NM_000322 phototransduction retinitis pigmentosa (ad, digenic with ROM1), macular degeneration (ad) Retina and anterior neural fold homeobox 2 RAX2 CORD11, RAXL1, 19p13.3 - NM_032753 transcription macular degeneration (isolated cases) ARMD6, QRX 11-cis retinol dehydrogenase 5 RDH5 RDH1 12q13.2 recessive NM_002905 chromophore metabolism late onset cone dystrophy (ar)

Table_3.xls 12.03.2010 1 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Rab3-interacting molecule 1 RIM1 CORD7, RIMS1, 6q13 dominant NM_014989 neurotransmitter release, cone rod dystrophy RAB3IP2, RIM exocytosis Retinitis pigmentosa GTPase regulator RPGR CORDX1, COD1, RP3, Xp11.4 recessive NM_000328 intraflagellar transport cone dystrophy, cone rod dystrophy, retinitis pigmentosa CRD, RP15 and (with deafness and sinorespiratory infections), macular dominant degeneration (Xlr, Xld) Retinitis pigmentosa GTPase regulator RPGRIP1 CORD13, RPGRIP, LCA6, 14q11.2 recessive NM_020366 interaction with retinitis cone rod dystrophy, Leber congenital amaurosis (ar) interacting protein 1 RGI1,RGRIP, RPGRIP1d pigmentosa GTPase regulator protein

Sema domain, immunoglobulin domain (Ig), SEMA4A CORD10, RP35, SEMAB, 1q22 recessive NM_022367 axon guidance cone rod dystrophy (ad, ar), retinitis pigmentosa (ad) transmembrane domain (TM) and short SemB and cytoplasmic domain, (semaphorin) 4A dominant

Syndromic cone and cone rod dystrophies (COD, CORD, progressive) Gene name Gene symbol Gene symbol aliases Chromos. Inheritance Ref.-seq. Potential function Clinical diagnosis Alstrom syndrome 1 ALMS1 ALSS, DKFZp686A118, 2p13 recessive NM_015120.4 component of Alstrom syndrome (ar) DKFZp686D1828, centrosome and cilia KIAA0328

Ataxin 7 ATXN7 ADCAII, OPCA3, SCA7 3p14.1 dominant NM_001128149 potential transcription spinocerebellar ataxia (ad) factor Bardet Biedl syndrome 1 gene BBS1 BBS2L2, FLJ23590, 11q13.1 recessive NM_024649 centrosomal and ciliary retinitis pigmentos (ar), Bardet Biedl syndrome 1 (ar) MGC51114, MGC126183, protein MGC126184

Cyclin M4 CNNM4 ACDP4, FLJ42791, 2q11.2 recessive NM_020184 potential metal Jalli syndrome (ar) KIAA1592 transporter Neurofibromin 1 NF1 FLJ21220, NFNS, VRNF, 17q11.2 dominant NM_000267 tumor suppressor neurofibromatosis (ad) WSS

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information

Table_3.xls 12.03.2010 2 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 4a: Non-syndromic and syndromic macular degenerations Non-syndromic macular degenerations (MD), ARMD not included Gene name Gene symbol Gene symbol aliases Chromososome Inheritance Ref.-seq. Potential function Additional diagnosis Retinal-specific ATP-binding cassette ABCA4 CORD3, FFM, STGD1, 1p22.1 recessive NM_000350 transport Stargardt disease (ar), retinitis pigmentosa (ar), cone rod transporter (ATP-binding cassette sub-family A RP19, ABCR, STGD, dystrophy (ar), juvenile and late onset macular member 4) ARMD2 degeneration (ar), fundus flavimaculatus (ar)

Bestrophin 1 BEST1 VMD2, ARB, BMD, 11q12.3 dominant NM_004183 anion channel autosomal dominant vitreoretinochoroidopathy; Best TU15B, macular dystrophy (BMD) (ad) complement C1q tumor necrosis factor-related C1QTNF5 CTRP5, LORD 11q23.3 dominant NM_015645 small collagen - protein 5 precursor variant 3 Cyclic nucleotide-gated cation channel beta-3 CNGB3 ACHM3 8q21.3 recessive NM_019098 phototransduction complete achromatopsia, typical achromatopsia, rod subunit monochromatism Fibulin 3 EFEMP1 FBNL, 3218, DHRD, S1- 2p16.1 dominant NM_004105 extracellular matrix Doyne honeycomb retinal degeneration 5, FBLN3, MTLV protein Elongation of very long chain fatty acids protein ELOVL4 STGD3, STGD2 6q14.1 dominant NM_022726 fatty acid metabolism - 4 Fascin homolog 2 FSCN2 RFSN, RP30 17q25.3 dominant NM_012418 photoreceptor disk mutations in FSCN2 may cause RP morphogenesis Guanylate cyclase activator 1B GUCA1B GCAP2 6p21.1 dominant NM_002098 phototransduction retinitis pigmentosa (ad) Hemicentin 1 HMCN1 ARMD1, FBLN6, FIBL-6, 1q31.1 dominant NM_031935 extracellular member of age-related macular degeneration FIBL6 the immunoglobulin superfamily

Prominin 1 PROM1 CORD12, CD133, RP41, 4p15.32 dominant NM_006017 cellular structure Stargardt disease (ad), retinitis pigmentosa (ar), cone rod STGD4, AC133, MCDR2, dystrophy (ad) PROML1 Peripherin-2 PRPH2 RP7, RDS, TSPAN22, 6p21.1 dominant NM_000322 photoreceptor outer cone dystrophy, cone rod dystrophy, retinitis pigmentosa rd2 segment structure (ad, digenic with ROM1), Retinitis pigmentosa GTPase regulator RPGR CORDX1, COD1, RP3, Xp11.4 recessive NM_000328 intraflagellar transport cone dystrophy, cone rod dystrophy, retinitis pigmentosa CRD, RP15 and dominant (with deafness and sinorespiratory infections), macular degeneration (Xlr, Xld) Retinoschisin RS1 RS, XLRS1 Xp22.13 recessive NM_000330 adhesion molecule? - Tissue inhibitor of metalloproteinases 3 TIMP3 SFD 22q12.3 dominant NM_000362 ECM remodelling? Sorsby fundus dystrophy (ad)

Syndromic macular degenerations (MD) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Ataxin 7 ATXN7 ADCAII, OPCA3, SCA7 3p14.1 dominant NM_001128149 potential transcription spinocerebellar ataxia (ad) factor Bardet Biedl syndrome 1 gene BBS1 BBS2L2, FLJ23590, 11q13.1 recessive NM_024649 centrosomal and ciliary retinitis pigmentos (ar), Bardet Biedl syndrome 1 (ar) MGC51114, MGC126183, protein MGC126184

Peroxisomal biogenesis factor 1 PEX1 IRD 7q21.2 recessive NM_000466 peroxisomal protein infantile form of phytanic acid storage disease import Peroxisomal biogenesis factor 26 PEX26 PEX26M1T, Pex26pM1T 22q11.21 recessive NM_017929 peroxisomal protein infantile form of phytanic acid storage disease import Peroxisomal membrane protein 3 PXMP3 PEX2, PMP35, PAF-1 8q21.11 recessive NM_000318 peroxisome biogenesis infantile form of phytanic acid storage disease

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information

Table_4a.xls 12.03.2010 1 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 4b: Age-related macular degeneration AMD associated genes Gene name Gene symbol Gene symbol aliases Chromosome Ref.-Seq. Potential function Additional diagnosis ATP-binding cassette sub-family A member 4 ABCA4 ARMD2, ABCR, CORD3, FFM, 1p22.1 NM_000350 transport Stargardt disease, retinitis pigmentosa, cone rod RP19, STGD, STGD1 dystrophy, juvenile and late onset macular degeneration, fundus flavimaculatus; all (ar) Apolipoprotein E APOE AD2, LDLCQ5, LPG, MGC1571 19q13.2 NM_000041 catabolism of triglyceride-rich lipoprotein familial dysbetalipoproteinemia (ad and ar), or type III hyperlipoproteinemia (HLP III) (ar and ad), end-stage renal disease (ESRD)(ad), Susceptibility to Alzheimer's disease Age-related maculopathy susceptibility 2 ARMS2 ARMD8 10q26.13 NM_001099667 mitochondrial outer membrane protein - Complement component 2 C2 DADB-122G4.1, CO2, 6p21.3 NM_000063 classical pathway of complement system - DKFZp779M0311 Complement component 3 C3 ARMD9, ASP, CPAMD1 19p13.3 NM_001735 activation of complement system Susceptibility to bacterial infection Complement factor B CFB DADB-122G4.5, BF, BFD, CFAB, 6p21.3 NM_001710 immune system; complement and coagulation - FB, FBI12, GBG, H2-Bf, PBF2 cascades

Complement factor H CFH ARMD4, ARMS1, CFHL3, HUS, 1q32 NM_000186 immune system; complement and coagulation atypical hemolytic uremic syndrome MGC88246 cascades Cystatin C CST3 ARMD11, MGC117328 20p11.21 NM_000099 extracellular inhibitor of cysteine proteases amyloid angiopathy AMD Excision repair cross-complementing rodent repair ERCC6 ARMD5, CKN2, COFS, COFS1, 10q11.23 NM_000124 DNA repair Cockayne syndrome type B (ar) deficiency CSB, RAD26 Fibulin 5 FBLN5 ARMD3, DANCE, EVEC, FIBL-5, 14q32.1 NM_006329 vascular development and remodeling autosomal dominant cutis laxa, cutis laxa type I (ar) FLJ90059, UP50 Hemicentin 1 HMCN1 ARMD1,FBLN6, FIBL-6, FIBL6 1q31.1 NM_031935 extracellular member of the immunoglobulin macular deheneration (ad) superfamily HtrA serine peptidase 1 HTRA1 ARMD7, HtrA, L56, ORF480, 10q26.3 NM_002775 regulation of availability of insulin-like growth - PRSS11 factors; regulator of cell growth Interleukin 8 IL-8 CXCL8, GCP-1, GCP1, LECT, 4q13-q21 NM_000634 mediators of inflammatory response; - LUCT, LYNAP, MDNCF, MONAP, chemoattractant; angiogenic factor NAF, NAP-1, NAP1 Pleckstrin homology domain containing, family A PLEKHA1 TAPP1 10q26.13 NM_021622 - -

Paraoxonase 1 PON1 ESA, PON 7q21.3 NM_000446 arylesterase risk factor in coronary artery disease and amylotrophic lateral sclerosis (ALS) retina and anterior neural fold homeobox 2 RAX2 ARMD6, CORD11, QRX, RAXL1 19p13.3 NM_032753 transcription cone-rod dystrophy type 11

Serpin peptidase inhibitor, clade G (C1 inhibitor), SERPING1 C1IN, C1INH, C1NH, HAE1, 11q12 NM_000062 regulation of the complement cascade hereditary angioneurotic oedema (HANE) (ar) member 1 HAE2 Toll-like receptor 3 TLR3 CD283 4q35 NM_003265 pathogen recognition and activation of innate - immunity Toll-like receptor 4 TLR4 ARMD10, CD284, TOLL, hToll 9q32 NM_138554 innate immune system lipopolysaccharide responsiveness Vascular endothelial growth factor A VEGFA RP1-261G23.1, MGC70609, 6p12 NM_001025366 vascular permeability, angiogenesis, diabetic retinopathy MVCD1, VEGF, VEGF-A, VPF vasculogenesis and endothelial cell growth, cell migration, apoptosis

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information

Table_4b.xls 12.03.2010 1

Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 5: Non-syndromic and syndromic generalized photoreceptor diseases Leber congenital amaurosis (LCAs) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Aryl-hydrocarbon-interacting protein-like 1 AIPL1 LCA4, AIPL2 17p13.1 recessive NM_014336 protein-protein interaction cone rod dystrophy (ad)

Centrosomal protein 290 CEP290 LCA10, SLSN6, MKS4, 12q21.32 recessive NM_025114 centrosomal and ciliary Senior Loken syndrome type 6 (ar), Meckel syndrome JBTS5, BBS14, NPHP6 protein type 4 (ar), Joubert syndrome type 5 (ar), Bardet Biedl syndrome type 14 (ar) Crumbs homolog 1 CRB1 LCA8, RP11, RP12 1q31.3 recessive NM_201253 tissue development and severe retinitis pigmentosa (ar), pigmented maintenance paravenous chorioretinal atrophy (ad), Cone-rod homeobox protein CRX LCA7, CORD2, CRD, 19q13.32 recessive NM_000554 transcription factor cone rod dystrophy (ad), retinitis pigmentosa (ad) OTX3 and rarely dominant Retinal guanylate cyclase 2D GUCY2D LCA1, CORD6, GUC1A4, 17p13.1 recessive NM_000180 phototransduction cone rod dystrophy (ad) GUC2D, LCA, retGC, CYGD, RETGC-1, ROS- GC1, CORD5 Inosine monophosphate dehydrogenase 1 IMPDH1 LCA11, IMPD, IMPD1, 7q32.1 recessive NM_000883 regulation of cell growth retinitis pigmentosa (ad) RP10 and rarely dominant Leber congenital amaurosis 5 LCA5 LCA5, C6ORF152, 6q14.1 recessive NM_181714 centrosomal protein with - Lebercillin ciliary function Lecithin retinol acyltransferase LRAT MGC33103 4q32.1 recessive NM_004744 retinal metabolism early-onset severe retinal dystrophy (ar) C-mer proto-oncogene tyrosine kinase MERTK MER, RP38, c-mer 2q14.1 recessive NM_006343 transmembrane protein retinitis pigmentosa (ar) Retinal degeneration 3 RD3 LCA12, C1ORF36 1q32.3 recessive NM_183059 transcription and splicing - Retinol dehydrogenase 12 RDH12 FLJ30273, LCA3, LCA13, 14q24.1 recessive NM_152443 phototransduction retinitis pigmentosa (ad) SDR7C2 Retinal pigment epithelium-specific protein RPE65 LCA2, RP20, 1p31.2 recessive NM_000329 visual cycle retinitis pigmentosa (ar) 65kDa Retinitis pigmentosa GTPase regulator RPGRIP1 LCA6, CORD13, RGI1, 14q11.2 recessive NM_020366 interaction with retinitis congenital blindness, cone rod dystrophy (ar) interacting protein 1 RGRIP, RPGRIP, pigmentosa GTPase RPGRIP1d regulator protein Spermatogenesis associated 7 SPATA7 HSD-3.1, HSD3, LCA3 14q31.3 recessive NM_018418 - juvenile retinitis pigmentosa (ar) Tubby like protein 1 TULP1 RP14, TUBL1 6p21.31 recessive NM_003322 tissue development and retinitis pigmentosa (ar) maintenance

Gyrate atrophy Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Ornithine aminotransferase OAT HOGA 10q26.13 recessive NM_000274 neurotransmitter metabolism -

Choroideremia Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Choroideremia protein CHM TCD, REP-1 Xq21.2 recessive NM_000390 protein prenylation -

Alagille syndrome Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Jagged1 JAG1 AGS 20p12.2 dominant NM_000214 development, notch signalling - Notch 2 receptor NOTCH2 hN2, AGS2 1p12 dominant NM_024408 development, notch signalling -

Neuronal ceroid lipofuscinosis (CLN), Batten disease

Table_5_incl_syndromic.xls 12.03.2010 1 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Battenin, Batten disease protein BTS CLN3, JNCL 16p12.1 recessive NM_000086 lysosomal protein - Ceroid-lipofuscinosis neuronal protein 5 CLN5 - 13q22.3 recessive NM_006493 unknown - Ceroid-lipofuscinosis neuronal protein 6 CLN6 - 15q23 recessive NM_017882 unknown - Ceroid-lipofuscinosis neuronal protein 7 CLN7 MFSD8 4q28.2 recessive NM_152778 lysosomal transporter - Ceroid-lipofuscinosis neuronal protein 8 CLN8 - 8p23 recessive NM_018941 ER / Glogi protein - Cathepsin D CTSD CLN10, CPSD 11p15.5 recessive NM_001909 intracellular protease - Palmitoyl-protein hydrolase 1 PPT1 CLN1, PPT 1p34.2 recessive NM_000310 lysosomal degradation macular degeneration, retinal degeneration Tripeptidyl-peptidase 1 TPP1 CLN2 11p15.4 recessive NM_000391 lysosomal protease -

Refsum disease Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Phytanoyl-CoA 2-hydroxylase PAHX PHYH, PHYH1 10p13 recessive NM_001037537 peroxisomal fatty acid - oxidation Peroxisome biogenesis factor 1 PEX1 IRD 7q21.2 recessive NM_000466 peroxisomal protein import - Peroxisome assembly protein 26 PEX26 FLJ20695, PEX26M1T, 22q11.21 recessive NM_017929 peroxisomal protein import - Pex26pM1T Peroxisomal targeting signal 2 receptor PEX7 PTS2R 6q23.3 recessive NM_000288 peroxisome biogenesis - peroxisomal membrane protein 3 PXMP3 PEX2, PMP35, PAF-1 8q21.11 recessive NM_000318 peroxisome biogenesis infantile form of phytanic acid storage disease

Joubert syndrome Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Abelson helper integration1 AHL1 JBTS3; ORF1; AHI-1 6q23.3 recessive NM_017651 - - ADP-ribosylation factor-like 13B ARL13B JBTS8, ARL2L1 3q11.2 recessive NM_182896 ciliary function - Coiled-coil and C2 domain containing 2A CC2D2A JBTS9, KIAA1345, MKS6 4p15.33 recessive NM_001080522 interaction with protein mental retardation with retinitis pigmentosa (ar) CEP290 Centrosomal protein 290 CEP290 LCA10, SLSN6, MKS4, 12q21.32 recessive NM_025114 centrosomal and ciliary Senior Loken syndrome type 6 (ar), Meckel syndrome JBTS5, BBS14, NPHP6 protein type 4 (ar), Bardet Biedl syndrome type 14 (ar), Leber congenital amaurosis type 10 (ar)

Nephronophthisis 1 NPHP1 JBTS4, SLSN1 2q13 recessive NM_000272 control of cell division, cell- - cell and cell-matrix adhesion signaling, complex in actin- and microtubule-based structures

Oral-facial-digital syndrome 1 OFD1 JBTS10 Xp22 recessive NM_003611 interacts with LCA5-encoded - lebercilin

RPGR-interacting protein 1-like protein RPGRIP1L JBTS7, KIAA1005, MKS5, 16q12.2 recessive NM_015272 localization to centrosome Meckel syndrome (ar) NPHP8 and primary cilia Transmembrane protein 67 TMEM67 JBTS6, MKS3, 8q24 recessive NM_153704 ciliary function Meckel syndrome (ar) Transmembrane protein 216 TMEM216 JBTS2 11q12.2 recessive NM_016499 -

Senior Loken syndrome Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Centrosomal protein 290 CEP290 LCA10, SLSN6, MKS4, 12q21.32 recessive NM_025114 centrosomal and ciliary Joubert syndrome 5 (ar), Meckel syndrome type 4 (ar), JBTS5, BBS14, NPHP6 protein Bardet Biedl syndrome type 14 (ar), Leber congenital amaurosis type 10 (ar)

Table_5_incl_syndromic.xls 12.03.2010 2 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Nephrocystin 1 NPHP1 SLSN1, JBTS4 2q13 recessive NM_000272 cell division, adhesion Nephronophthisis (ar), Joubert syndrome type 4 (ar)

Nephrocystin 2 NPHP2 INVS, inversin 9q31 recessive NM_183245 cell cycle Nephronophthisis (ar) Nephrocystin 3 NPHP3 SLSN3 3q22.1 recessive NM_153240 unknown Nephronophthisis (ar) Nephrocystin 4, Nephroretinin NPHP4 SLSN4 1p36.31 recessive NM_015102 unknown Nephronophthisis (ar) Nephrocystin 5 NPHP5 SLSN5, IQCB1 3q13.33 recessive NM_001023570 unknown Nephronophthisis (ar)

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information available

Table_5_incl_syndromic.xls 12.03.2010 3 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 6: Exudative and erosive vitreoretinopathies Non-syndromic exudative vitreoretinopathies (EVR) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Frizzled-4 FZD4 EVR1, CD344 11q14.2 dominant NM_012193 Wnt signalling - Low-density lipoprotein receptor-related protein 5 LRP5 EVR4, OPPG, OPS, 11q13.2 recessive NM_002335 Wnt signalling Osteoporosis pseudoglioma syndrome (OPPG, ar), LR3, BMND1 osteoporosis (ad), bone mineral density quantitative trait locus Norrin NDP EVR2 Xp11.3 X-linked NM_000266 Ligand of FZD4 and Norrie disease pseudoglioma (Xlr), retinopathy of recessive LRP5 prematurity (ROP) Tetraspanin 12 TSPAN12 TM4SF12, NET-2 7q31.31 dominant NM_012338 Norrin-coreceptor -

Non-syndromic erosive vitreoretinopathies (ERVR) Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Bestrophin 1 BEST1 VMD2, ARB, BMD, 11q12.3 dominant NM_004183 anion channel autosomal dominant vitreoretinochoroidopathy; Best TU15B, macular dystrophy (BMD) (ad) Potassium inwardly-rectifying channel KCNJ13 KIR1.4, KIR7.1, 2q37 dominant NM_002242 potassium channels snowflake vitreoretinal degeneration (SVD) (ad) MGC33328, SVD Nuclear receptor subfamily 2, group E, member 3 NR2E3 ESCS, MGC49976, 15q22.32 dominant NM_016346 transcription factor enhanced S cone syndrome (ESCS) (ad and ar); PNR, RNR, RP37, rd7 retinitis pigmentosa type 37 (ad); Goldmann-Favre Syndrome Versican VCAN CSPG2, ERVR, PG-M, 5q14.3 dominant NM_004385 hyaluronic acid binding, Wagner syndrome 1, ERVR (ad) WGN, WGN1 extracellular matrix

Syndromic Vitreoretinopathies Stickler syndrome Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Collagen, type II, alpha 1 COL2A1 ANFH, AOM, 12q13.11 dominant NM_001844 extracellular matrix achondrogenesis, chondrodysplasia, early onset COL11A3, familial osteoarthritis, SED congenita, Langer-Saldino MGC131516, SEDC achondrogenesis, Kniest dysplasia, and spondyloepimetaphyseal dysplasia Strudwick type (ad and ar) Collagen, type XI, alpha 1 COL11A1 CO11A1, COLL6, STL2 1p21 dominant NM_001854 extracellular matrix Marshall syndrome (ad)

Collagen, type XI, alpha 2 COL11A2 DADB-100D22.2, 6p21.3 dominant NM_080680 extracellular matrix otospondylomega-epiphyseal dysplasia (OSMED DFNA13, DFNB53, syndrome) (ad), Weissenbacher-Zweymuller HKE5, PARP, STL3 syndrome (ar), non-syndromic sensorineural type 13 deafness (DFNA13) (ad), non-syndromic sensorineural type 53 deafness (DFNB53) (ar)

Collagen, type IX, alpha 1 COL9A1 RP1-138F4.2, 6q12-q14 recessive NM_001851 structural association with - DJ149L1.1.2, EDM6, collagen type II and XI FLJ40263, MED

Norrie disease pseudoglioma Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Norrin NDP EVR2 Xp11.3 X-linked NM_000266 Ligand of FZD4 and Norrie disease pseudoglioma (Xlr), retinopathy of recessive LRP5 prematurity (ROP)

Table_6.xls 12.03.2010 1 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Osteoporosis pseudoglioma syndrome Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function Additional diagnosis Low-density lipoprotein receptor-related protein 5 LRP5 EVR4, OPPG, OPS, 11q13.2 recessive NM_002335 Wnt signalling Osteoporosis pseudoglioma syndrome (OPPG, ar), LR3, BMND1 osteoporosis (ad), bone mineral density quantitative trait locus

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information available

Table_6.xls 12.03.2010 2 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Table 8: Syndromic, rod dominated retinal degenerations Bardet Biedl syndrome Gene name Gene symbol Gene symbol aliases Chromosome Inheritance Ref.-seq. Potential function additional phenotype Bardet Biedl Syndrome gene 1 BBS1 BBS2L2, FLJ23590, 11q13.1 recessive NM_024649 centrosomal and ciliary retinitis pigmentosa (ar), macular degeneration (ar), MGC51114, protein cone rod dystrophy (ar) MGC126183, MGC126184 Bardet Biedl Syndrome gene 2 BBS2 MGC20703 16q13 recessive NM_031885 cilia formation and function -

Bardet Biedl Syndrome gene 3 BBS3 ARL6 3q11.2 recessive NM_032146 ciliary transport - Bardet Biedl Syndrome gene 4 BBS4 - 15q24.1 recessive NM_033028 basal bodies and cetriolar - statelites Bardet Biedl Syndrome gene 5 BBS5 - 2q31.1 recessive NM_152384 basal bodies - Bardet Biedl Syndrome gene 6 BBS6 MKKS, HMCS, KMS, 20p12.2 recessive NM_018848 protein folding McKusick-Kaufmann syndrome (ar) MKS Bardet Biedl Syndrome gene 7 BBS7 BBS2L1, FLJ10715 4q27 recessive NM_176824 cilia formation and function -

Bardet Biedl Syndrome gene 8 BBS8 TTC8 14q31.3 recessive NM_144596 basal bodies and - centrosomes Bardet Biedl Syndrome gene 9 BBS9 PTHB1, MGC118917 7p14.3 recessive NM_198428 cilia formation and function -

Bardet Biedl Syndrome gene 10 BBS10 C12orf58, FLJ23560 12q21.2 recessive NM_024685 protein folding - Bardet Biedl Syndrome gene 11 BBS11 TRIM32, HT2A, TATIP, 9q33.1 recessive NM_012210 proteasome degradation - LGMD2H Bardet Biedl Syndrome gene 12 BBS12 C4orf24, FLJ35630, 4q27 recessive NM_152618 protein folding - FLJ41559 Bardet Biedl Syndrome gene 14 CEP290 BBS14, LCA10, 12q21.32 recessive NM_025114 centrosomal and ciliary Senior Loken syndrome (ar), Meckel syndrome (ar), SLSN6, MKS4, JBTS5, protein Joubert syndrome (ar), LCA (ar) NPHP6

ADP-ribosylation factor-like 13B ARL13B JBTS8, ARL2L1 3q11.2 recessive NM_182896 ciliary function - Coiled-coil and C2 domain containing 2A CC2D2A JBTS9, KIAA1345, 4p15.33 recessive NM_001080522 interaction with protein mental retardation with retinitis pigmentosa (ar) MKS6 CEP290 Centrosomal protein 290 CEP290 JBTS5, BBS14, LCA10, 12q21.32 recessive NM_025114 localized to centrosome and Senior Loken syndrome type 6 (ar), Leber congenital MKS4, NPHP6, SLSN6 cilia, interaction with protein amaurosis (LCA10, ar), Meckel syndrome type 4 CC2D2A (ar),Bardet Biedl syndrome 14 (ar)

Nephronophthisis 1 NPHP1 JBTS4, SLSN1 2q13 recessive NM_000272 control of cell division, cell- - cell and cell-matrix adhesion signaling, complex in actin- and microtubule-based structures

Table_8.xls 12.03.2010 1 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Oral-facial-digital syndrome 1 OFD1 JBTS10 Xp22 recessive NM_003611 interacts with LCA5-encoded - lebercilin

RPGR-interacting protein 1-like protein RPGRIP1L JBTS7, KIAA1005, 16q12.2 recessive NM_015272 localization to centrosome Meckel syndrome (ar) MKS5, NPHP8 and primary cilia

Transmembrane protein 67 TMEM67 JBTS6, MKS3, 8q24 recessive NM_153704 ciliary function Meckel syndrome (ar) Transmembrane protein 216 TMEM216 HSPC244 11q12.2 recessive NM_016499 ciliary function -

Primary ciliary dyskinesias (PCD) Gene name Gene symbol Gene symbol aliases Chromososome Inheritance Ref.-seq. Potential function Additional diagnosis Axonemal dynein heavy chain 11 DNAH11 DPL11, DNAHC11, 7p15.3 recessive NM_003777 motor ATPase - 2942, DNAHBL, DNHBL, CILD7 Axonemal dynein heavy chain 5 DNAH5 HL1, KTGNR, 2950, 5p15.2 recessive NM_001369 - DNAHC5, CILD3, PCD

Axonemal dynein intermediate chain 1 DNAI1 CILD1, PCD 9p13.3 recessive NM_012144 - Axonemal dynein intermediate chain 2 DNAI2 CILD9 17q25.1 recessive NM_023036 - Kintoun KTU C14orf104, 20188, 14q22.1 recessive NM_018139 - FLJ10563 Thioredoxin domain-containing protein 3 TXNDC3 CILD6, NME8, SPTRX2 7p14.1 recessive NM_016616 protein disulfide reductase -

Refsum disease Gene name Gene symbol Gene symbol aliases Chromososome Inheritance Ref.-seq. Potential function Additional diagnosis Phytanoyl-CoA 2-hydroxylase PAHX PHYH, PHYH1 10p13 recessive NM_001037537 peroxisomal fatty acid adult form oxidation Peroxisomal biogenesis factor 1 PEX1 IRD 7q21.2 recessive NM_000466 peroxisomal protein import infantile form of phytanic acid storage disease

Peroxisomal targeting signal 2 receptor PEX7 PTS2R 6q23.3 recessive NM_000288 peroxisome biogenesis adult form peroxisomal biogenesis factor 26 PEX26 PEX26M1T, 22q11.21 recessive NM_017929 peroxisomal protein import infantile form of phytanic acid storage disease Pex26pM1T Peroxisome assembly factor 1 (PAF-1), PXMP3 PEX2, PMP35, PAF-1 8q21.11 recessive NM_000318 peroxisome biogenesis infantile form of phytanic acid storage disease Peroxin-2

Senior Loken syndrome Gene name Gene symbol Gene symbol aliases Chromososome Inheritance Ref.-seq. Potential function Additional diagnosis Centrosomal protein 290 CEP290 SLSN6, MKS4, JBTS5, 12q21.32 recessive NM_025114 centrosomal and ciliary Leber congenital amaurosis (LCA10, ar), Meckel NPHP6, BBS14, LCA10 protein syndrome type 4 (ar), Joubert syndrome 5 (ar), Bardet Biedl syndrome 14 (ar) Nephrocystin 1 NPHP1 SLSN1, JBTS4 2q13 recessive NM_000272 cell division, adhesion Nephronophthisis (ar), Joubert syndrome type 4 (ar)

Nephrocystin 2 NPHP2 INVS 9q31 recessive NM_183245 cell cycle Nephronophthisis (ar) Nephrocystin 3 NPHP3 SLSN3 3q22.1 recessive NM_153240 - Nephronophthisis (ar) Nephrocystin 4, Nephroretinin NPHP4 SLSN4 1p36.31 recessive NM_015102 - Nephronophthisis (ar) Nephrocystin 5 NPHP5 SLSN5, IQCB1 3q13.33 recessive NM_001023570 - Nephronophthisis (ar)

Table_8.xls 12.03.2010 2 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010) Usher syndrome (USH) Gene name Gene symbol Gene symbol aliases Chromososome Inheritance Ref.-seq. Potential function Additional diagnosis Clarin-1 CLRN1 USH3A 3q25.1 recessive NM_052995 ribbon synapse? - Clarin-3 CLRN3 USH3AL1, TMEM12 10q26.2 recessive NM_152311 - - Deafness, autosomal recessive 31 DFNB31 USH2D, CIP98, WHRN, 9q32 recessive NM_001083885 - deafness (ar) DFNB31 G-protein coupled receptor 98 GPR98 USH2C, FEB4, MASS1, 5q14.3 recessive NM_032119 - - VLGR1b Myosin-VIIa MYO7A USH1B, NSRD2, 11q13.5 recessive NM_000260 vesicle trafficking, transport deafness (ar) DFNA11, DFNB2 Protocadherin-15 PCDH15 USH1F, DFNB23 10q21.1 recessive NM_001142764 cell adhesion deafness (ar), digenic Usher syndrome with CDH23

Usher syndrome type-1G protein SANS USH1G, ANKS4A 17q25.1 recessive NM_173477 scaffold protein - Harmonin USH1C AIE-75, PDZ73, PDZ- 11p15.1 recessive NM_005709 - deafness (ar) 73, DFNB18 Cadherin-23 Precursor, Otocadherin USH1D CDH23, DFNB12 10q22.1 recessive NM_052836 cell adhesion deafness (ar), digenic Usher syndrome with PCDH15

Usher syndrome 2A USH2A USH2, RP39 1q41 recessive NM_206933 cellular structure retinitis pigmentosa (ar)

For references see the corresponding section in this review or the Retnet website. ad: autosomal dominant; ar: autosomal recessive; - : no information available

Table_8.xls 12.03.2010 3 Berger et al., Manuscript for Progress in Retinal and Eye Research, (amended March 12 2010)