Perspective on Genes and Mutations Causing Retinitis Pigmentosa

SPECIAL ARTICLE Perspective on Genes and Mutations Causing Retinitis Pigmentosa

Stephen P. Daiger, PhD; Sara J. Bowne, PhD; Lori S. Sullivan, PhD

xceptional progress has been made during the past two decades in identifying genes causing inherited retinal diseases such as retinitis pigmentosa. An inescapable consequence is that the relationship between genes, mutations, and clinical findings has become very complex. Success in identifying the causes of inherited retinal diseases has Emany implications, including a better understanding of the biological basis of vision and insights into the processes involved in retinal pathology. From a clinical point of view, there are two important questions arising from these developments: where do we stand today in finding disease- causing mutations in affected individuals, and what are the implications of this information for clinical practice? This perspective addresses these questions specifically for retinitis pigmentosa, but the observations apply generally to other forms of inherited eye disease. Arch Ophthalmol. 2007;125:151-158

The goal of this perspective is to summa- nopathies can be found at the RetNet Web rize the current state of the molecular di- site.1 A number of recent reviews address agnosis of retinitis pigmentosa (RP) and the biological bases of RP.2-5 its relevance to clinical practice. The com- Retinitis pigmentosa encompasses ments are limited largely to nonsyn- many different diseases with many dis- dromic, nonsystemic forms of RP, using tinct causes and diverse biological path- autosomal dominant RP (adRP) as an ex- ways but with overlapping symptoms and ample. It is important to recognize, though, similar consequences.4 It is no more a that what is true for simple RP is true in single disease than is “fever of unknown general for most other forms of inherited origin.” If one word more than any other retinal degeneration. There has been rapid comes to mind in describing RP, it is com- progress in identifying genes and muta- plicated. There are dominant, recessive, and tions causing all forms of retinal disease, X-linked forms of inheritance in addition including multifactorial diseases such as to rare mitochondrial and digenic forms. age-related macular degeneration. Of Retinitis pigmentosa may occur alone or course, the specific genes are different and as part of a more complex syndrome. Even the clinical findings are distinct, but the simple RP is strikingly complicated. Each implications for clinical practice are simi- genetic type is caused by mutations in sev- lar. For example, what is true for RP alone eral or many different genes. For most is also true for Usher syndrome, Bardet- genes, many different mutations with simi- Biedl syndrome, and familial macular de- lar consequences are known, yet other mu- generation. That is, many genes and mutations in the same gene may cause dif- tations are also known for these diseases ferent diseases. Perhaps most surprisingly, and have relevance to clinical practice. A the same mutation in different individu- list of genes causing RP and other reti- als may cause distinctly different symp- Author Affiliations: Department of Ophthalmology and Visual Science, School of toms, even among individuals within the Medicine (Dr Daiger) and Human Genetics Center, School of Public Health same family. (Drs Daiger, Bowne, and Sullivan), The University of Texas Health Science Center, Ironically, the great success in identify- Houston, Tex. ing genes and mutations causing RP dur-

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 151 Downloaded from www.archophthalmol.com at University of Pittsburgh, on August 11, 2009 ©2007 American Medical Association. All rights reserved. sion and eventually legal blindness tions and, hence, in the proportion Table 1. Prevalence of Retinitis or, in many cases, complete blind- of specific genetic types. Therefore, Pigmentosa and Estimated ness. Clinical hallmarks are an ab- the proportions in Table 1 should be Percentages of Retinitis Pigmentosa Types6,10 normal fundus with bone-spicule de- taken with a grain of salt. posits and attenuated retinal vessels; Nonsyndromic, nonsystemic RP %of abnormal, diminished, or absent encompasses 65% of all cases, or Category Type Total* electroretinographic findings; and about 65 000 people in the United Nonsyndromic Autosomal 20 reduced visual fields. Symptoms States. Of the total number of non- RP dominant RP typically start in the early teenage syndromic, nonsystemic cases, Autosomal 13 years, and severe visual impair- roughly 30% are adRP, 20% are au- recessive RP ment occurs by ages 40 to 50 years. tosomal recessive RP, 15% are X- X-linked RP 8 However, there are early-onset forms linked RP, and 5% are early-onset Isolated or 20 unknown RP of RP (the earliest is indistinguish- forms of RP that are typically diag- Leber congenital 4 able from Leber congenital amau- nosed as recessive LCA. The remain- amaurosis rosis [LCA]) and other late-onset or ing cases, at least 30%, are isolated or Subtotal 65 even nonpenetrant forms. The un- simplex cases. The simplex cases are Syndromic and Usher syndrome 10 derlying genetic cause is a useful pre- likely to include many individuals systemic RP dictor of severity in some cases, but with recessive mutations, but domi- Bardet-Biedl 5 syndrome the inverse is usually not true: the nant-acting de novo mutations are 11,12 Other 10 phenotype alone is not a good pre- also found in these individuals. Subtotal 25 dictor of the gene or mutation. In the past few decades, rapid Other or 10 In addition to simple forms of RP, progress has been made in finding unknown there are syndromic forms involv- genes and mutations causing inher- types of RP Figure Total 100 ing multiple organs and pleiotro- ited retinal diseases. The pic effects as well as systemic forms shows the progress in gene identi- 1 Abbreviation: RP, retinitis pigmentosa. wherein the retinal disease is sec- fication since 1980. Genes and the *The total prevalence is 1 case per 3100 ondary to a systemwide pathology underlying mutations within these persons (range, 1 case per 3000 persons to (although the distinction is more his- genes have been identified by a num- 1 case per 7000 persons), or 32.2 cases per 100 000 persons.10 toric than biological). The most fre- ber of methods. Many genes were quent form of syndromic RP is Usher first localized to a chromosomal site syndrome, which manifests as early- by linkage mapping in families or, ing the past 2 decades has revealed onset or congenital hearing impair- more recently, by homozygosity the extent of the complexity but also ment followed by development of RP mapping.13,14 Once mapped, the un- offers hope of taming it—by defin- by the early teenage years.7,8 The sec- derlying gene can be found by vari- ing RP at a molecular level rather than ond most common syndromic form ous targeted sequencing strategies. clinically. Still, in spite of the progress is Bardet-Biedl syndrome, which in- Other disease genes were identified in genetics, a careful clinical descrip- cludes RP, polydactyly, obesity, re- by sequencing candidate genes in se- tion is and will be an essential pre- nal abnormalities, and mental retar- lected patient populations. A reti- requisite for molecular diagnosis. dation.9 In addition, many other nal gene may be a disease candi- Further, the molecular description complex, pleiotropic conditions in- date because of its functional of RP is intrinsically complicated. clude RP as a component.1 properties, because it is similar to a Molecular diagnosis alone will there- Table 1 shows the overall preva- gene known to cause retinal dis- fore neither replace clinical testing lence of RP and the proportions of ease, or because it is the cause of reti- nor fully resolve the complexity. the most common genetic sub- nal disease in an animal model. Nonetheless, clinical testing coupled types. Retinitis pigmentosa, broadly To date, 181 genes causing in- with molecular diagnosis of RP defined to include simple, syn- herited retinal diseases have been is a powerful combination of ap- dromic, and systemic disease, has a mapped to a specific chromosomal proaches for diagnosing patients and worldwide prevalence of 1 case per site, and 129 of these have been iden- families and will eventually lead to 3000 persons to 1 case per 7000 per- tified at a sequence level. Also, at treatment and prevention. sons.10 This is a relatively narrow least 5 additional genes are known range of estimates given the inher- to contribute to the lifetime risk of SUMMARY OF GENES AND ent difficulty of counting RP cases multifactorial diseases such as age- MUTATIONS CAUSING RP in large populations. In contrast, es- related macular degeneration.15-22 timates of the fractions of the vari- What is true for retinal disease Retinitis pigmentosa is a class of dis- ous genetic subtypes vary 10-fold be- genes in general is especially true for eases involving progressive degen- tween studies (summarized by RP. Currently, mutations in 17 dif- eration of the retina, typically start- Haim10). Part of the reason is that ferent genes are known to cause ing in the midperiphery and definitions and clinical criteria dif- adRP, mutations in 25 genes cause advancing toward the macula and fo- fer significantly between surveys. recessive RP, mutations in 13 genes vea.6 Typical symptoms include However, there are also substantial cause recessive LCA, mutations in night blindness followed by decreas- differences between populations in 2 genes cause dominant LCA, and ing visual fields, leading to tunnel vi- the prevalence of specific muta- mutations in 6 genes cause X-linked

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140

120

100

60 Retinal Disease Genes, No.

0 January January January January January January January January January January January January January January 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006

Figure. Number of mapped and identified retinal disease genes from 1980 to 2006.

RP.1 Table 2 lists the genes that are veys. A gene is “major” if it accounts genic mutations in 25% to 90% of currently known to cause nonsyn- for at least 1% of cases. In summary, patients, an extraordinary accom- dromic, nonsystemic RP. However, with a number of simplifying assump- plishment. At the same time, how- a simple listing of genes in each cat- tions, it is now possible to detect dis- ever, linkage studies and other evi- egory is misleading because many ease-causing mutations in 56% of pa- dence show that that there are more, genes can cause more than 1 form tients with adRP, roughly 30% of perhaps many more, RP genes to be of disease. For example, although patients with recessive RP, more than found. rhodopsin mutations usually cause 70% of patients with recessive LCA, dominant RP, other rare rhodopsin and nearly 90% of patients with X- GENES AND MUTATIONS mutations cause recessive RP. Mu- linked RP. This is a remarkable CAUSING adRP tations in NRL can also be either achievement given that the first gene dominant or recessive acting. Fur- known to cause RP, the rhodopsin To give a more detailed perspec- ther, mutations in some genes, such gene, was described only 17 years tive, what follows is a look at the as RDS, can cause dominant RP, ago.40,41 genes and mutations causing just 1 dominant macular degeneration, or The percentages in Table 3 come form of retinal disease, adRP. How- other distinct forms of retinopathy. with several caveats. First, many of ever, many of the conclusions from Therefore, Table 2 also lists the al- the numbers are “soft” because dis- the study of adRP are broadly appli- ternate phenotypes that can arise for ease definitions are not consistent cable to other inherited retinal dis- mutations in RP genes and lists some between reports, sample sizes may eases. Therefore, this section ends genes in more than 1 section. be small, different segments of the with observations that apply gener- In total, mutations in 53 genes are gene may have been screened, and ally to all forms of RP. known to cause nonsyndromic, non- the definition of a mutation differs In a recent survey, we tested a systemic RP or LCA (counting each significantly from study to study. panel of affected individuals from gene once only, even if it causes In fact, very few published percent- 200 families with adRP for muta- more than 1 type of retinopathy). As ages include confidence intervals, tions in most of the known domi- stunning as this number may be, a which are usually large. Further, nant RP genes (Table 2).23 To be in- question more important than the most of these studies are of cluded in the study, a family had to number of genes is the total frac- Americans of European origin and have a diagnosis of adRP by a knowl- tion of patients in whom disease- Europeans. Other ethnic and geo- edgeable clinical specialist and either causing mutations can be detected. graphic groups have different frac- 3 affected generations with affected In other words, how close are we to tions of disease-causing muta- females or 2 affected generations knowing all of the RP genes? tions.42,43 Finally, these are the with male-to-male transmission. The One way to answer this question fractions of mutations detected in latter requirement was to reduce the is to summarize the fraction of mu- carefully designed studies with op- likelihood of including families with tations detected in each gene based on timal methods; screening in prac- X-linked RP. This possibility arises surveys of appropriate patient popu- tice may be less efficient. because some mutations in the lations. Table 3 is a compilation of But caveats aside, across all of the X-linked gene RPGR affect female the percentage of patients with de- categories of inherited retinopathy, carriers; thus, the disease in these tectable mutations in each major RP careful screening of known disease families can be misinterpreted as gene as reported in representative sur- genes leads to detection of patho- adRP.44-46

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 153 Downloaded from www.archophthalmol.com at University of Pittsburgh, on August 11, 2009 ©2007 American Medical Association. All rights reserved. The cohort of patients with adRP Table 2. Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic was screened (largely by DNA se- * Retinitis Pigmentosa quencing) for mutations in the protein-coding regions and intron- Symbol Location Protein Other Diseases exon junctions of all adRP genes or Autosomal Dominant RP gene regions causing at least 1% of CA4 17q23.2 Carbonic anhydrase IV None cases. Open reading frame 15 CRX 19q13.32 Cone-rod homeobox Recessive LCA, dominant LCA, dominant CORD (ORF15), the “hot spot” for domi- FSCN2 17q25.3 Fascin homolog 2, actin-bundling None nant-acting mutations in RPGR, was protein, retinal also tested in families without male- GUCA1B 6p21.1 Guanylate cyclase activator 1B Dominant MD to-male transmission. Determining (retina) whether a novel, rare variant is IMPDH1 7q32.1 IMP (inosine monophosphate) Dominant LCA 47 dehydrogenase 1 pathogenic can be challenging. We NRL 14q11.2 Neural retina leucine zipper Recessive RP used several computational and ge- PRPF3 1q21.2 PRP3 pre-mRNA processing factor 3 None netic tools for this purpose.23 Gen- homolog (Saccharomyces erally, once a definite disease- cerevisiae) PRPF8 17p13.3 PRP8 pre-mRNA processing factor 8 None causing mutation was identified in homolog (S cerevisiae) a family, other genes were not tested PRPF31 19q13.42 PRP31 pre-mRNA processing factor None further in these individuals. 31 homolog (S cerevisiae) We found definite or probable RDS 6p21.2 Retinal degeneration, slow Digenic RP with retinal outer mutations in 53.5% of the families (peripherin 2) segment membrane protein 1, dominant MD with adRP. In subsequent studies, we RHO 3q22.1 Rhodopsin Recessive RP, dominant CSNB tested several of the remaining fami- ROM1 11q12.3 Retinal outer segment membrane Digenic RP with retinal lies for linkage to genetic markers protein 1 degeneration, slow within or close to the known adRP RP1 8q12.1 RP-1 protein Recessive RP genes and to RPGR.24 The logic here RP9 7p14.3 RP-9 (autosomal dominant) None RP31 9p22-p13 Unknown None was to uncover mutations that might RP33 2cen-q12.1 Unknown None have been missed by sequencing or SEMA4A 1q22 Sema domain, immunoglobulin Dominant CORD to locate genes that have been domain (Ig), transmembrane mapped but not identified yet. In 1 domain (TM), and short large family, we found linkage to the cytoplasmic domain (semiphorin) 4A PRPF31 gene, even though careful resequencing failed to disclose a Autosomal Recessive RP ABCA4 1p22.1 ATP-binding cassette, subfamily A Recessive MD, recessive DNA change. Further testing re- (ABC1), member 4 CORD vealed that affected members of the CERKL 2q31.3 Ceramide kinase–like protein None family have a complex deletion and CNGA1 4p12 Cyclic nucleotide gated channel ␣1 None insertion in PRPF31. This rearrange- CNGB1 16q13 Cyclic nucleotide gated channel ␤1 None ment was not detected earlier be- CRB1 1q31.3 Crumbs homolog 1 Recessive LCA LRAT 4q32.1 Lecithin retinol acyltransferase Recessive LCA cause only the nondeleted, homolo- MERTK 2q13 C-mer proto-oncogene tyrosine None gous chromosome was sequenced; kinase that is, the deletion is “invisible” to NR2E3 15q23 Nuclear receptor subfamily 2, group Recessive enhanced S-cone sequencing. E, member 3 syndrome We then tested the remaining NRL 14q11.2 Neural retina leucine zipper Dominant RP PRCD 17q25.1 Progressive rod-cone degeneration None families for deletions in PRPF31 us- gene ing multiplex ligation-dependent PDE6A 5q33.1 Phosphodiesterase 6A, None probe amplification (MLPA).48,49 Sur- cGMP-specific, rod, ␣ prisingly, we found 4 large dele- PDE6B 4p16.3 Phosphodiesterase 6B, Dominant CSNB ␤ tions, including 2 that encompass cGMP-specific, rod, 24 RGR 10q23.1 Retinal G protein–coupled receptor Dominant choroidal sclerosis genes adjacent to PRPF31. This RHO 3q22.1 Rhodopsin Dominant RP brings the fraction of detected mu- RLBP1 15q26.1 Retinaldehyde-binding protein 1 Recessive Bothnia dystrophy tations to 56% (Table 3). RP1 8q12.1 RP-1 protein Dominant RP These studies have a number of RP22 16p12.3-p12.1 Unknown None implications that go beyond just RP25 6cen-q15 Unknown None RP28 2p16-p11 Unknown None adRP. First, 14 different, common RP29 4q32-q34 Unknown None mutations account for up to 30% of RP32 1p34.3-p13.3 Unknown None the families with adRP in this sur- RPE65 1p31.2 RPE-specific 65-kd protein Recessive LCA vey; that is, each of these muta- SAG 2q37.1 S-antigen; retina and pineal gland Recessive Oguchi disease tions accounts for at least 1% of the (arrestin) 23 TULP1 6p21.31 Tubby-like protein 1 Recessive LCA cases. Thus, screening for this USH2A 1q41 Usher syndrome 2A Recessive Usher syndrome handful of mutations alone will resolve at least 30% of the cases. Com- (continued) mon mutations are found in other

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 154 Downloaded from www.archophthalmol.com at University of Pittsburgh, on August 11, 2009 ©2007 American Medical Association. All rights reserved. RP genes, and numerous inexpensive, high-throughput techniques ex- Table 2. Genes and Mapped Loci Causing Nonsyndromic, Nonsystemic * ist for detecting these variants.50,51 Retinitis Pigmentosa (cont) Second, another 20% of mutations were novel and could only be Symbol Location Protein Other Diseases detected by sequencing entire genes. Autosomal Recessive LCA Further, each novel mutation re- AIPL1 17p13.2 Arylhydrocarbon-interacting Dominant CORD receptor protein-like 1 quires careful evaluation of patho- CEP290 12q21.32 Centrosomal 290-kd protein Recessive Senior-Loken genicity. As a consequence, the main syndrome, recessive bottleneck in genetic testing of pa- Joubert syndrome tients with RP is the need to screen CRB1 1q31.3 Crumbs homolog 1 Recessive RP and analyze many genes by expen- CRX 19q13.32 Cone-rod homeobox Dominant CORD, dominant LCA, dominant RP sive, time-consuming methods. For- GUCY2D 17p13.1 Guanylate cyclase 2D, membrane Dominant CORD tunately, promising high-through- (retina-specific) put resequencing techniques, such LRAT 4q32.1 Lecithin retinol acyltransferase Recessive RP as microarray gene chips, may re- LCA3 14q24 Unknown None lieve this bottleneck.52 Nonethe- LCA5 6q11-q16 Unknown None LCA9 1p36 Unknown None less, interpretation of novel, rare RDH12 14q24.1 Retinol dehydrogenase 12 None variants will still require profes- RPE65 1p31.2 RPE-specific 65-kd protein Recessive RP sional evaluation.47 RPGRIP1 14q11.2 RP GTPase regulator interacting None Third, some families thought to protein 1 have adRP actually have digenic or TULP1 6p21.31 Tubby-like protein 1 Recessive RP X-linked mutations. Digenic RP is Autosomal Dominant LCA the result of 1 mutation in RDS and CRX 19q13.32 Cone-rod homeobox Dominant CORD, recessive 53 LCA, dominant RP a second in ROM1. Different indi- IMPDH1 7q32.1 IMP (inosine monophosphate) Dominant RP vidual mutations in RDS and ROM1 dehydrogenase 1 can cause adRP, but each of the di- X-Linked RP genic mutations alone is not patho- RP2 Xp11.23 RP-2 protein None genic. Digenic and polygenic inher- RP6 Xp21.3-p21.2 Unknown None itance is true of other forms of retinal RP23 Xp22 Unknown None disease, such as Bardet-Biedl syn- RP24 Xq26-q27 Unknown None drome, which can be “triallelic.”9 RP34 Xq28-qter Unknown None RPGR Xp11.4 RP GTPase regulator X-linked COD, X-linked CSNB Another misleading mode of inheritance among families diagnosed Abbreviations: ATP, adenosine triphosphate; cGMP, cyclic guanosine monophosphate; COD, cone with “adRP” is X-linked inherit- dystrophy; CORD, cone-rod dystrophy; CSNB, congenital stationary night blindness; GTPase, guanosine ance of RPGR mutations with sig- triphosphatase; LCA, Leber congenital amaurosis; MD, macular dystrophy; mRNA, messenger RNA; nificant disease in carrier fe- RP, retinitis pigmentosa; RPE, retinal pigment epithelium. *References are in RetNet (http://www.sph.uth.tmc.edu/RetNet/). males.44-46 Both of these phenomena are important reminders that the molecular diagnosis can radically lies in the frequency and segregation ered. Completion of the Human change genetic counseling. of RP mutations. If so, here again, the Genome Project, new high-through- Fourth, at least 2.5% of adRP mu- molecular diagnosis will affect coun- put screening methods, and devel- tations are genomic rearrangements seling. Finally, this finding suggests opment of powerful bioinformatic or deletions in PRPF31 that are not that there may be other subtle muta- approaches have dramatically re- detectable by conventional screen- tions in known RP genes that are duced the time it will take to find new ing methods.24 Whether there are dis- missed by standard methods. genes. In spite of these technical ad- ease-causing deletions in other adRP Fifth, there are definitely addi- vances, the need for thorough, genes or in recessive or X-linked tional, unknown adRP genes. We knowledgeable, innovative clinical genes is an active area of research. failed to detect mutations in 40% of characterization of patients and fami- This is likely, though, because dele- the families we tested. Some, but not lies has never been greater. tions are a common cause of other in- all, of the remaining mutations may herited and acquired diseases.54-56 For be deletions or subtle changes in RELEVANCE TO CLINICAL example, large deletions cause up to known genes that have not been de- PRACTICE AND FUTURE 17% of familial breast cancer.57 tected to date.58 Linkage mapping DIRECTIONS The existence of disease-causing continues to locate new adRP deletions has significant implica- genes—most recently RP31 and What does the current state of RP ge- tions for molecular testing of pa- RP33.59,60 Likewise, new recessive netics say of the future? A reason- tients with RP. For one, routine test- and X-linked genes are reported able hope is that within 5 years, mo- ing methods may miss deletions (eg, regularly.1 lecular testing of newly diagnosed sequencing does not detect the breast It is impossible to predict whether patients with RP will be a routine part cancer deletions). For another, dele- there are several or many more RP of clinical practice and will uncover tions may explain reported anoma- genes that have yet to be discov- the underlying disease-causing mu-

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 155 Downloaded from www.archophthalmol.com at University of Pittsburgh, on August 11, 2009 ©2007 American Medical Association. All rights reserved. There are several compelling rea- Table 3. Mutations in Genes That Cause an Appreciable Fraction of Retinitis sons why molecular testing is impor- Pigmentosa Cases tant for clinical care. For one, identifying the underlying mutation(s) % of All Cases Symbol in Disease Category Source can establish the diagnosis, which may be problematic otherwise. This Autosomal Dominant RP is particularly important for child- CRX 1.0 Sullivan et al,23 2006 IMPDH1 2.5 Sullivan et al,23 2006 hood retinopathies wherein the mo- PRPF3 1.0 Sullivan et al,23 2006 lecular diagnosis may portend dis- PRPF8 3.0 Sullivan et al,23 2006 tinctly different clinical outcomes.33,61 PRPF31 8.0 Sullivan et al,23 2006; Also, knowing the genetic cause is es- Sullivan et al,24 2006 sential for family counseling and for 23 RDS 9.5* Sullivan et al, 2006 predicting recurrence risk and prog- RHO 26.5 Sullivan et al,23 2006 RP1 3.5 Sullivan et al,23 2006 nosis. In addition, each new muta- RPGR 1.0 Sullivan et al,23 2006 tion that is found contributes to a bet- Total 56.0 ter understanding of ocular biology. Autosomal Recessive RP Finally and of the most importance, ABCA4 2.9 Klevering et al,25 2004 the era of gene-specific and mutation- CNGA1 2.3 Dryja et al,26 1995 specific treatments for inherited reti- CRB1 6.5† Bernal et al,27 2003 nal diseases is quickly approach- CRX 1.0 Rivolta et al,28 2001 ing.62,63 Knowing the underlying 29 PDE6A 4.0 Dryja et al, 1999 genetic cause will be essential for en- PDE6B 4.0 McLaughlin et al,30 1995 RPE65 2.0 Morimura et al,31 1998 rolling patients in clinical trials, a few USH2A 10.0 Seyedahmadi et al,32 2004 of which have begun already or will 64,65 Total 32.7 begin shortly. It is a safe predic- Autosomal Recessive LCA tion that in the near future, there will AIPL1 3.4 Hanein et al,33 2004 be many more treatment and preven- CEP290 21.0 den Hollander et al,34 2006 tion strategies based on knowledge CRB1 10.0 Hanein et al,33 2004 of the underlying mutation(s) in af- GUCY2D 21.2 Hanein et al,33 2004 fected individuals and families. RDH12 4.1 Perrault et al,35 2004 33 Then, how close are we to rou- RPE65 6.1 Hanein et al, 2004 tine molecular diagnosis of RP? RPGRIP1 4.5 Hanein et al,33 2004 TULP1 1.7 Hanein et al,33 2004 Identification of new RP genes is pro- Total 72.0 ceeding swiftly. An educated guess (at best) is that most of the major Autosomal Dominant LCA CRX Ϸ1 Perrault et al,36 2003; genes, at least in Americans of Eu- Sohocki et al,37 1998 ropean origin and Europeans, will IMPDH1 Ϸ1 Bowne et al,11 2006 be found within 5 to 10 years. Total Unknown Whether current screening meth- X-Linked RP ods, such as sequencing or micro- RP2 15.1 Pelletier et al,38 2006 array testing, can detect all or even RPGR 74.2 Pelletier et al,38 2006‡ most of the mutations in known Total 89.3 genes is debatable. Not all of the gene regions that could harbor muta- Abbreviations: adRP, autosomal dominant retinitis pigmentosa; LCA, Leber congenital amaurosis; RP, retinitis pigmentosa. tions are tested routinely. For ex- *Includes 1 family with digenic RDS-ROM1 mutations. ample, large intervening sequences †Up to 50% of recessive RP with Coats disease or para-arteriolar preservation of the retinal pigment and noncoding regulatory regions epithelium.39 ‡Includes families with X-linked retinitis pigmentosa not linked to RP2 or RPGR. are usually ignored. Also, current methods do not detect large deletions or rearrangements. Ventur- ing another educated guess, though, tation (or mutations) in at least 90% 4. We must be able to under- existing methods and methods un- of cases. For this hope to come true, stand, interpret, and explain the mo- der development will be able to de- 4 conditions must be met: lecular information. tect most mutations, ie, more than 1. Most of the genes causing RP Before addressing these neces- 90%, within 5 years. must be identified. sary conditions, it is worth asking Currently, the greatest road- 2. It must be possible to detect why finding the underlying disease- block to molecular diagnosis of RP nearly all of the disease-causing mu- causing mutation should matter to is the availability of genetic testing. tations within these genes. the patient or the clinician. After all, Large commercial interests have not 3. Mutation testing must be- RP is currently an untreatable con- yet entered the field, primarily become inexpensive, reliable, and dition, so wouldn’t the molecular in- cause there are so many genes to test widely available. formation be of no use? and so many inherent complica-

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 156 Downloaded from www.archophthalmol.com at University of Pittsburgh, on August 11, 2009 ©2007 American Medical Association. All rights reserved. tions. However, methods for rapid, thalmology profession will lead the mentosa and Leber congenital amaurosis. Invest inexpensive detection of known RP way for other branches of medicine. Ophthalmol Vis Sci. 2006;47:34-42. 12. Schwartz SB, Aleman TS, Cideciyan AV, Swaroop mutations exist today and will be A, Jacobson SG, Stone EM. De novo mutation in 51,66 routinely available soon. Also, Submitted for Publication: Septem- the RP1 gene (Arg677ter) associated with retini- targeted screening of genes and gene ber 14, 2006; final revision re- tis pigmentosa. Invest Ophthalmol Vis Sci. 2003; regions that are frequent causes of ceived September 29, 2006; ac- 44:3593-3597. inherited retinal diseases is being of- 13. Lathrop GM, Lalouel JM, Julier C, Ott J. Strate- cepted October 2, 2006. gies for multilocus linkage analysis in humans. fered on a fee-for-service basis by a Correspondence: Stephen P. Daiger, Proc Natl Acad SciUSA. 1984;81:3443-3446. few institutions in the United States PhD, Human Genetics Center, 14. Sheffield VC, Nishimura DY, Stone EM. Novel ap- and Europe (see the GeneTests Web School of Public Health, 1200 Her- proaches to linkage mapping. Curr Opin Genet Dev. site for further information67). In ad- man Pressler Dr, The University of 1995;5:335-341. 15. Edwards AO, Ritter R III, Abel KJ, Manning A, Pan- dition, the National Eye Institute has Texas Health Science Center, Hous- huysen C, Farrer LA. Complement factor H poly- recently developed a program, ton, TX 77030-3900 (stephen.p morphism and age-related macular degeneration. eyeGENETM,68 to facilitate genetic [email protected]). Science. 2005;308:421-424. testing of inherited eye diseases. Fi- Financial Disclosure: None re- 16. Gold B, Merriam JE, Zernant J, et al. Variation in nally, it is reasonable to expect that ported. factor B (BF) and complement component 2 (C2) genes is associated with age-related macular new high-throughput sequencing Funding/Support: This study was degeneration. Nat Genet. 2006;38:458-462. methods will make genetic testing of supported by grants from the Foun- 17. Haines JL, Hauser MA, Schmidt S, et al. Comple- all diseases affordable and efficient dation Fighting Blindness, the Wil- ment factor H variant increases the risk of age- within 10 years.69 liam Stamps Farish Foundation, the related macular degeneration. Science. 2005; In our opinion, the major 308:419-421. Gustavus and Louise Pfeiffer Re- 18. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Fer- impediment to routine molecular search Foundation, and the Her- rell RE, Gorin MB. Susceptibility genes for age- diagnosis of RP is not technical or mann Eye Fund as well as by grants related maculopathy on chromosome 10q26. 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