Eye (2007) 21, 1344–1351 & 2007 Nature Publishing Group All rights reserved 0950-222X/07 $30.00 www.nature.com/eye 1,2 1,2,3 CAMBRIDGE OPHTHALMOLOGY SYMPOSIUM Molecular genetics P Moradi and AT Moore of infantile-onset retinal dystrophies Abstract either novel proteins or proteins that have hitherto not been suspected to play a role in Over the last decade there have been major retinal function. The discovery of these genes advances in our understanding of the has highlighted the role of new biological molecular pathology of inherited retinal pathways in retinal structure and function. The dystrophies. This paper reviews recent identification of the genes underlying inherited advances in the identification of genetic retinal disease is an important first step in mutations underlying infantile-onset understanding the mechanism of retinal inherited retinal disorders and considers dysfunction and in developing effective how this knowledge may lead to novel treatment. It also has a more immediate impact therapeutic approaches. on clinical management in improving diagnosis Eye (2007) 21, 1344–1351; doi:10.1038/sj.eye.6702843 and genetic counselling. This review aims to discuss the various Keywords: retina; inherited; paediatric; gene infantile-onset retinal dystrophies including achromatopsia, blue cone monochromatism (BCM), congenital stationary night blindness Introduction (CSNB), and Leber’s congenital amaurosis (LCA). The inherited retinal disorders are historically classified according to natural history (stationary or progressive), the mode of Achromatopsia inheritance (autosomal dominant (AD), autosomal recessive (AR), X linked (XL), or Achromatopsia is a genetically heterogeneous mitochondrial), and principal site of retinal group of AR stationary retinal disorders in dysfunction (pigment epithelium, rod or cone which there is an absence of functioning cones photoreceptor, or inner retina). Such in the retina.1 Affected individuals have classification involves careful history and reduced central vision, poor colour vision, 1 Institute of Ophthalmology examination, and detailed psychophysical and photophobia, pendular nystagmus, and usually UCL, London, UK electrophysiological assessment. Such a method normal fundi. Achromatopsia may occur in of subdividing retinal disease is however complete (typical) and incomplete (atypical) 2Moorfields Eye Hospital London, London, UK unsatisfactory as it may not reflect the forms. molecular pathology of the retinal dysfunction. Complete achromatopsia (rod 3Hospital for Sick Children Advances in molecular genetics of retinal monochromatism) has an incidence of Great Ormond St London, disease have allowed a more precise approximately 1 in 30 000. The disorder is London, UK classification based on the genetic mutations inherited as an AR trait. The usual presentation underlying the disorders. is with early infantile-onset of nystagmus, poor Correspondence: AT Moore, Rapid advances have been made in the field visual acuity, and sensitivity to light. Vision is Richard Desmond Childrens Eye Centre, Moorfields Eye of retinal molecular genetics since the discovery improved in mesopic conditions. Pupil Hospital, City Road, London of causative genes began in 1989. The database reactions are slow and may show paradoxical EC1V 2PD at Retnet (http://www.retnet.org) lists over responses (pupillary dilation to bright light). Tel: þ 44 207 566 2260; 30 identified genes of inherited retinal A hypermetropic refractive error is common. Fax: þ 44 207 566 2019. dysfunction not including the syndromic forms The nystagmus often improves with age, as E-mail: tony.moore@ 2 ucl.ac.uk of retinal dystrophies. Some of these genes can the photophobia. Fundus examination is encode proteins with a well characterised generally normal; however, macular atrophy Received: 12 March 2007 function in the retina, for example may occasionally be present. Adults with Accepted: 22 March 2007 phototransduction, but other genes encode this disorder usually achieve a visual acuity Molecular genetics of retinal dystrophies P Moradi and AT Moore 1345 of 6/60 to 6/36 and have no true colour vision, to be responsible for less than 2% of patients affected although affected individuals may be able to distinguish with achromatopsia. primary colours using brightness clues. Rod-specific The three genes,CNGA3, CNGB3, and GNAT2 together ERGs are normal but there are no detectable cone- account for the majority of cases of achromatopsia, but it derived responses.3 Psychophysical testing reveals that is likely that there are one or more genes that account for retinal function is determined by rod photoreceptors a minority of cases. Uniparental isodisomy of alone. chromosome 14 has been reported in association with Incomplete achromatopsia is best used to describe an achromatopsia like phenotype23 suggesting that individuals with AR disease where the phenotype is there may be an additional achromatopsia gene on a variant of complete achromatopsia. Individuals with chromosome 14. However, recently a homozygous this variant have better acuity (6/24 to 6/60) and mutation in CNGB3 has been identified in the original retain some residual colour vision.4 patient with the chromosome 14 rearrangement Three achromatopsia genes have been identified to indicating that it is unlikely that there is a further date, CNGA3, CNGB3, and GNAT2. All encode locus on chromosome 14.24 components of the cone photo-transduction cascade. Mutations in all three genes have been reported in Blue cone monochromatism association with complete achromatopsia,5–8 whereas only mutations in CNGA3 have been identified in Blue cone (S-cone) monochromatism affects less than one incomplete achromatopsia.9 in 100 000 individuals; it is characterised by absence of CNGA3 and CNGB3, encode the a- and b-subunits L and M cone function.25 There is normal rod and short of the cGMP-gated (CNG) cation channel in cone cells. wavelength sensitive cone function . BCM presents in The cGMP levels are high in cone photoreceptors in infancy with reduced visual acuity, pendular nystagmus, the dark, which enables binding to the a- and b-subunits and photophobia.26 The nystagmus often reduces with of CNG channels. This permits an open channel time. Affected individuals are usually myopic and conformation, cation influx, and cone depolarisation. best-corrected visual acuity is usually in the range of At photopic levels, activated photopigments initiate a 6/24 to 6/60. Fundus examination is usually normal, but cascade producing increased cGMP-phosphodiesterase macular atrophy is seen in some older individuals. BCM activity. As a result, the level of cGMP is reduced in may be distinguished from achromatopsia by the mode the photoreceptor, which leads to closure of CNG cation of inheritance, the presence of a myopic rather than channels and cone hyperpolarisation. Mutations in hyperopic refractive error and by the results of detailed CNGA3 and CNGB3 account for the majority of cases psychophysical and electrophysiological testing. The of achromatopsia10–12 There are over 50 disease-causing photopic ERG is profoundly reduced in both disorders, mutations in CNGA3 that have been identified in but the S cone ERG is normal in BCM.27 Psychophysical patients with achromatopsia13,14 with the majority being testing in BCM shows evidence of normal S-cone missense sequence variants. The CNGA3 gene is highly function in comparison to rod monochromats where conserved in evolution and it appears that there is little there is either completely absent cone function or in tolerance for substitutions with respect to the function incomplete forms some residual L- or M-cone function. of the channel polypeptide. Four mutations (Arg227Cys, In clinical practice it is important to use colour vision Arg283Trp, Arg436Trp, and Phe547Leu) account for tests that probe the tritan colour axis as well as the protan approximately 40% of all mutant CNGA3 alleles.,15 By and deutan to distinguish RM and BCM; residual tritan comparison, approximately only 12 mutations have been discrimination suggests the latter diagnosis.28,29 identified in CNGB3,16–18 with the majority being The normal human visual system compares the rate nonsense variants. The most frequent CNGB3 mutation of quantum catches in three classes of cones; the short (S) to date, a 1 base-pair frameshift deletion 1148delC wavelength sensitive, middle (M) wavelength sensitive, (Thr383fs), accounts for 80% of CNGB3 mutant disease and long (L) wavelength sensitive to light at 430, 535, chromosomes.19,20 and 565 nm respectively. The L (red) and M (green) A third gene, GNAT2, which encodes the a-subunit pigment genes are located on the X chromosome and the of cone transducin, has also been implicated in S cone (blue) pigment is encoded by a gene located on achromatopsia.21,22 In cone cells, light-activated chromosome 7.30 The L and M opsin genes consist of a photopigment interacts with transducin, a three tandem array of two or more repeat units of 39 kb on subunit guanine nucleotide binding protein, stimulating chromosome Xq28 that are 98% identical at the DNA the exchange of bound GDP for GTP. The GNAT2 level31,32 Mutations in the L and M gene array underlie mutations result in premature translation termination the molecular pathology of BCM.33 Such mutations are and in protein truncation. GNAT2 mutations are thought of two main types. In the first group, the locus control Eye Molecular genetics of retinal dystrophies P Moradi and AT Moore 1346 region (LCR) (which is common for both normal L and M Two genes, CACNA1F and NYX, have been implicated pigment gene arrays), upstream of the L pigment gene is in XL CSNB. Incomplete CSNB is associated with deleted. The deletion abolishes transcription of all genes mutations in CACNA1F. This gene encodes the retina- in the pigment gene array and inactivates L and M specific a1F-subunit of the voltage-gated L-type calcium cones.34 In the second group of mutations, the LCR is channel; it is expressed in the outer and inner nuclear preserved, but changes within the L and M pigment gene layer and the ganglion cell layer.47,48 Most of the array lead to loss of functional pigment production.