perspective on genes and mutations causing retinitis pigmentosa (2007)

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SPECIAL ARTICLE

Perspective on Genes and MutationsCausing Retinitis PigmentosaStephen P. Daiger, PhD; Sara J. Bowne, PhD; Lori S. Sullivan, PhD

E xceptional progress has been made during the past two decades in identifying genescausing inherited retinal diseases such as retinitis pigmentosa. An inescapable conse-quence is that the relationship between genes, mutations, and clinical findings has be-come very complex. Success in identifying the causes of inherited retinal diseases has

many 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 im-portant 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 forclinical 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-rize the current state of the molecular di-agnosis of retinitis pigmentosa (RP) andits relevance to clinical practice. Thecom-ments are limited largely to nonsyn-dromic, nonsystemic forms of RP, usingautosomal dominant RP (adRP) as an ex-ample.It is important to recognize, though,that what is true for simple RP is true ingeneral for most other forms of inheritedretinal degeneration.There hasbeen rapidprogress in identifying genes and muta-tions causing all forms of retinal disease,including multifactorial diseases such asage-related macular degeneration. Of course, the specific genes are different andthe clinical findings are distinct, but theimplications for clinical practice are simi-lar. For example, what is true for RP aloneis also true for Usher syndrome, Bardet-Biedl syndrome, and familial macular de-generation. That is, many genes and mu-tations are also known for these diseasesand have relevance to clinical practice. Alist of genes causing RP and other reti-

nopathiescan be foundat theRetNet Website.1 A number of recent reviews addressthe biological bases of RP. 2-5

Retinitis pigmentosa encompassesmany different diseases with many dis-tinct causes and diverse biological path-ways but withoverlappingsymptoms andsimilar consequences. 4 It is no more asingle disease than is “fever of unknownorigin.” If one word more than any othercomes to mind in describing RP, it is complicated. Therearedominant, recessive, andX-linked forms of inheritance in additionto rare mitochondrial and digenic forms.Retinitis pigmentosa may occur alone oraspart ofa morecomplex syndrome. EvensimpleRP is strikingly complicated.Eachgenetic type is causedby mutations in sev-

eral or many different genes. For mostgenes, many different mutations withsimi-larconsequences areknown, yet other mu-tations in the same gene may cause dif-ferentdiseases.Perhaps mostsurprisingly,the same mutation in different individu-als may cause distinctly different symp-toms, even among individuals within thesame family.

Ironically, the great success in identify-ing genes and mutations causing RP dur-

Author Affiliations: Department of Ophthalmology and Visual Science, School of Medicine (Dr Daiger) and Human Genetics Center, School of Public Health(Drs Daiger, Bowne, and Sullivan), The University of Texas Health Science Center,Houston, Tex.

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ing the past 2 decades has revealedtheextentof thecomplexity butalsooffers hope of taming it—by defin-ingRP atamolecular levelratherthanclinically.Still,in spiteoftheprogressin genetics, a careful clinicaldescrip-

tion is and will be an essential pre-requisite for molecular diagnosis.Further, the molecular descriptionof RP is intrinsically complicated.Molecular diagnosis alone will there-fore neither replace clinical testingnor fully resolve the complexity.Nonetheless, clinical testingcoupledwith molecular diagnosis of RPis a powerful combination of ap-proachesfordiagnosing patientsandfamilies and will eventually lead totreatment and prevention.

SUMMARY OF GENES ANDMUTATIONS CAUSING RP

Retinitis pigmentosa is a class of dis-eases involving progressive degen-eration of the retina, typically start-ing in the midperiphery andadvancing toward themaculaandfo-vea. 6 Typical symptoms includenight blindness followedby decreas-ingvisual fields, leading to tunnelvi-

sion and eventually legal blindnessor, in many cases, complete blind-ness. Clinical hallmarks are an ab-normal funduswith bone-spiculede-posits andattenuated retinal vessels;abnormal, diminished, or absentelectroretinographic findings; andreduced visual fields. Symptomstypically start in the early teenage

years, and severe visual impair-ment occurs by ages 40 to 50 years.However, there areearly-onset formsof RP (the earliest is indistinguish-able from Leber congenital amau-rosis [LCA]) andother late-onset oreven nonpenetrant forms. The un-derlyinggenetic cause isa useful pre-dictor of severity in some cases, butthe inverse is usually not true: thephenotype alone is not a good pre-dictor of the gene or mutation.

Inaddition to simple formsofRP,there are syndromic forms involv-

ing multiple organs and pleiotro-pic effects as well as systemic formswherein the retinal disease is sec-ondary to a systemwide pathology(although thedistinction ismore his-toric than biological).The most fre-quent formofsyndromicRPisUshersyndrome,which manifestsas early-onset or congenital hearing impair-mentfollowedbydevelopment ofRPby theearly teenage years. 7,8 Thesec-ondmost common syndromic formis Bardet-Biedl syndrome, which in-cludes RP, polydactyly, obesity, re-

nal abnormalities, andmental retar-dation. 9 In addition, many othercomplex,pleiotropic conditions in-clude RP as a component. 1

Table 1 shows theoverall preva-lence of RP and the proportions of the most common genetic sub-types.Retinitis pigmentosa,broadlydefined to include simple, syn-dromic, and systemic disease, has aworldwide prevalence of 1 case per3000persons to1 caseper 7000per-sons. 10 This is a relatively narrowrange of estimates given the inher-

ent difficulty of counting RP casesin large populations. In contrast, es-timates of the fractions of the vari-ousgeneticsubtypes vary10-fold be-tween studies (summarized byHaim 10). Part of the reason is thatdefinitions and clinical criteria dif-fer significantly between surveys.However, there are also substantialdifferences between populations inthe prevalence of specific muta-

tions and, hence, in the proportionof specific genetic types. Therefore,theproportions inTable 1 shouldbetaken with a grain of salt.

Nonsyndromic, nonsystemic RPencompasses 65% of all cases, orabout 65 000 people in the UnitedStates. Of the total number of non-syndromic, nonsystemic cases,

roughly 30% are adRP, 20% are au-tosomal recessive RP, 15% are X-linked RP, and 5% are early-onsetforms of RP that are typically diag-nosedas recessive LCA. Theremain-ing cases, at least30%, areisolated orsimplex cases.The simplex cases arelikely to include many individualswith recessive mutations, but domi-nant-acting de novo mutations arealso found in these individuals. 11,12

In the past few decades, rapidprogress has been made in findinggenes and mutations causing inher-

ited retinal diseases. The Figureshows the progress in gene identi-fication since 1980. 1 Genes and theunderlying mutations within thesegeneshavebeen identifiedbya num-ber of methods. Many genes werefirst localized to a chromosomal siteby linkage mapping in families or,more recently, by homozygositymapping. 13,14 Once mapped, theun-derlying gene can be found by vari-ous targeted sequencing strategies.Other disease genes were identifiedbysequencing candidategenes in se-

lected patient populations. A reti-nal gene may be a disease candi-date because of its functionalproperties, because it is similar to agene known to cause retinal dis-ease, orbecause it is the cause ofreti-nal disease in an animal model.

To date, 181 genes causing in-herited retinal diseases have beenmapped to a specific chromosomalsite,and 129 of thesehave beeniden-tified at a sequence level. Also, atleast 5 additional genes are knownto contribute to the lifetime risk of

multifactorial diseases such as age-related macular degeneration. 15-22

What is true for retinal diseasegenes ingeneral is especially trueforRP. Currently, mutations in 17 dif-ferent genes are known to causeadRP, mutations in 25 genes causerecessive RP, mutations in 13 genescause recessive LCA, mutations in2 genes cause dominant LCA, andmutations in 6 genes cause X-linked

Table 1. Prevalence of RetinitisPigmentosa and EstimatedPercentages of RetinitisPigmentosa Types 6,10

Category Type% of

Total*

NonsyndromicRP

Autosomaldominant RP

20

Autosomalrecessive RP

13

X-linked RP 8Isolated or

unknown RP20

Leber congenitalamaurosis

4

Subtotal 65Syndromic and

systemic RPUsher syndrome 10

Bardet-Biedlsyndrome

5

Other 10Subtotal 25

Other orunknowntypes of RP

10

Total 100

Abbreviation: RP, retinitis pigmentosa.* The total prevalence is 1 case per 3100

persons (range, 1 case per 3000 persons to1 case per 7000 persons), or 32.2 cases per100000 persons.10





RP.1 Table 2 lists thegenes that are

currently known to cause nonsyn-dromic, nonsystemic RP. However,a simple listing of genes in each cat-egory is misleading because manygenes can cause more than 1 formof disease. For example, althoughrhodopsin mutations usually causedominant RP, other rare rhodopsinmutations cause recessive RP. Mu-tations in NRL can also be eitherdominant or recessive acting. Fur-ther, mutations in some genes, suchas RDS, can cause dominant RP,dominant macular degeneration, or

other distinct forms of retinopathy.Therefore, Table 2 also lists the al-ternatephenotypes thatcanarise formutations inRPgenesandlistssomegenes in more than 1 section.

In total, mutations in53genesareknown to cause nonsyndromic,non-systemic RP or LCA(countingeachgene once only, even if it causesmore than 1 typeof retinopathy). Asstunning as this number may be, aquestion more important than thenumber of genes is the total frac-tion of patients in whom disease-

causing mutations can be detected.In other words, how close are we toknowing all of the RP genes?

One way to answer this questionis to summarize the fraction of mu-tationsdetectedin eachgenebasedonsurveys of appropriate patient popu-lations. Table 3 is a compilation of the percentage of patients with de-tectable mutations in each major RPgeneasreportedinrepresentative sur-

veys. A gene is “major” if it accounts

for at least 1% of cases. In summary,witha numberofsimplifyingassump-tions, it isnowpossible to detectdis-ease-causing mutations in56%ofpa-tients with adRP, roughly 30% of patientswith recessiveRP,more than70% of patients with recessive LCA,and nearly 90% of patients with X-linked RP. This is a remarkableachievement given that thefirst geneknown to cause RP, the rhodopsingene, was described only 17 yearsago.40,41

Thepercentages in Table 3 come

with several caveats. First, many of the numbers are “soft” because dis-ease definitions are not consistentbetween reports, sample sizes maybe small, different segments of thegene may have been screened, andthe definition of a mutation differssignificantly from study to study.In fact, very fewpublishedpercent-ages include confidence intervals,which are usually large. Further,mos t o f these s tud ies a re of Americans of European origin andEuropeans. Other ethnic and geo-

graphic groups have different frac-tions of disease-causing muta-tions. 42,43 Finally, these are thefractions of mutations detected incarefully designed studies with op-timal methods; screening in prac-tice may be less efficient.

But caveatsaside, across all of thecategories of inherited retinopathy,careful screening of known diseasegenes leads to detection of patho-

genic mutations in 25% to 90% of

patients, an extraordinary accom-plishment. At the same time, how-ever, linkage studies and other evi-dence showthat that there are more,perhaps many more, RP genes to befound.

GENES AND MUTATIONSCAUSING adRP

To give a more detailed perspec-tive, what follows is a look at thegenes and mutations causing just 1form of retinal disease, adRP. How-

ever, many of the conclusions fromthestudy of adRP arebroadly appli-cable to other inherited retinal dis-eases. Therefore, this section endswith observations that apply gener-ally to all forms of RP.

In a recent survey, we tested apanel of affected individuals from200 families with adRP for muta-tions in most of the known domi-nant RP genes (Table 2). 23 Tobe in-cluded in the study, a family had tohavea diagnosis ofadRPbya knowl-edgeable clinical specialist andeither

3 affected generations with affectedfemales or 2 affected generationswithmale-to-maletransmission.Thelatter requirement was to reduce thelikelihood of includingfamilieswithX-linked RP. This possibility arisesbecause some mutations in theX-linked gene RPGR affect femalecarriers; thus, the disease in thesefamilies can be misinterpreted asadRP. 44-46

100

120

140

160

180

80

60

40

20

0January

1980January

1982January

1994January

1984January

1996January

1986January

1998January

1988January

2000January

1990January

2002January

1992January

2004January

2006

R e t i n a

l D i s e

a s e

G e n e s

, N o

.

MappedIdentified

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





Thecohort ofpatientswith adRPwas screened (largely by DNA se-quencing) for mutations in thepro-tein-coding regions and intron-exon junctions of all adRP genes orgene regions causing at least 1% of cases. Open reading frame 15(ORF15), the “hot spot” for domi-nant-actingmutations in RPGR,was

also tested in families without male-to-male transmission. Determiningwhether a novel, rare variant ispathogeniccan be challenging. 47 Weused several computational and ge-netic tools for this purpose. 23 Gen-erally, once a definite disease-causing mutation was identified ina family, other genes were not testedfurther in these individuals.

We found definite or probablemutations in 53.5% of the familieswith adRP. In subsequentstudies, wetestedseveral of the remainingfami-

lies for linkage to genetic markerswithin or close to the known adRPgenesandto RPGR.24 Thelogic herewas touncovermutations that mighthave been missed by sequencing orto locate genes that have beenmapped but not identified yet. In 1large family, we found linkage to thePRPF31 gene, even though carefulresequencing failed to disclose aDNA change. Further testing re-vealed that affected members of thefamilyhave a complex deletion andinsertion in PRPF31. This rearrange-

ment was not detected earlier be-cause only the nondeleted, homolo-gous chromosome was sequenced;that is, the deletion is “invisible” tosequencing.

We then tested the remainingfamilies for deletions in PRPF31 us-ing multiplex ligation-dependentprobeamplification (MLPA). 48,49 Sur-prisingly, we found 4 large dele-tions, including 2 that encompassgenes adjacent to PRPF31.24 Thisbrings the fraction of detected mu-tations to 56% (Table 3).

These studies have a number of implications that go beyond justadRP. First, 14 different, commonmutations account for up to 30% of the families with adRP in this sur-vey; that is, each of these muta-tions accounts for at least 1% of thecases. 23 Thus, screening for thishandful of mutations alone will re-solve at least 30% of thecases. Com-mon mutations are found in other

Table 2. Genes and Mapped Loci Causing Nonsyndromic, NonsystemicRetinitis Pigmentosa *

Symbol Location Protein Other Diseases

Autosomal Dominant RPCA4 17q23.2 Carbonic anhydrase IV NoneCRX 19q13.32 Cone-rod homeobox Recessive LCA, dominant

LCA, dominant CORDFSCN2 17q25.3 Fascin homolog 2, actin-bundling

protein, retinalNone

GUCA1B 6p21.1 Guanylate cyclase activator 1B(retina)

Dominant MD

IMPDH1 7q32.1 IMP (inosine monophosphate)dehydrogenase 1

Dominant LCA

NRL 14q11.2 Neural retina leucine zipper Recessive RPPRPF3 1q21.2 PRP3 pre-mRNA processing factor 3

homolog (Saccharomyces cerevisiae )

None

PRPF8 17p13.3 PRP8 pre-mRNA processing factor 8homolog (S cerevisiae )

None

PRPF31 19q13.42 PRP31 pre-mRNA processing factor31 homolog (S cerevisiae )

None

RDS 6p21.2 Retinal degeneration, slow(peripherin 2)

Digenic RP with retinal outersegment membraneprotein 1, dominant MD

RHO 3q22.1 Rhodopsin Recessive RP, dominant CSNB

ROM1 11q12.3 Retinal outer segment membraneprotein 1 Digenic RP with retinaldegeneration, slowRP1 8q12.1 RP-1 protein Recessive RPRP9 7p14.3 RP-9 (autosomal dominant) NoneRP31 9p22-p13 Unknown NoneRP33 2cen-q12.1 Unknown NoneSEMA4A 1q22 Sema domain, immunoglobulin

domain (Ig), transmembranedomain (TM), and shortcytoplasmic domain(semiphorin) 4A

Dominant CORD

Autosomal Recessive RPABCA4 1p22.1 ATP-binding cassette, subfamily A

(ABC1), member 4Recessive MD, recessive

CORDCERKL 2q31.3 Ceramide kinase–like protein NoneCNGA1 4p12 Cyclic nucleotide gated channel1 NoneCNGB1 16q13 Cyclic nucleotide gated channel1 NoneCRB1 1q31.3 Crumbs homolog 1 Recessive LCALRAT 4q32.1 Lecithin retinol acyltransferase Recessive LCAMERTK 2q13 C-mer proto-oncogene tyrosine

kinaseNone

NR2E3 15q23 Nuclear receptor subfamily 2, groupE, member 3

Recessive enhanced S-conesyndrome

NRL 14q11.2 Neural retina leucine zipper Dominant RPPRCD 17q25.1 Progressive rod-cone degeneration

geneNone

PDE6A 5q33.1 Phosphodiesterase 6A,cGMP-specific, rod,

None

PDE6B 4p16.3 Phosphodiesterase 6B,cGMP-specific, rod,

Dominant CSNB

RGR 10q23.1 Retinal G protein–coupled receptor Dominant choroidal sclerosisRHO 3q22.1 Rhodopsin Dominant RPRLBP1 15q26.1 Retinaldehyde-binding protein 1 Recessive Bothnia dystrophyRP1 8q12.1 RP-1 protein Dominant RPRP22 16p12.3-p12.1 Unknown NoneRP25 6cen-q15 Unknown NoneRP28 2p16-p11 Unknown NoneRP29 4q32-q34 Unknown NoneRP32 1p34.3-p13.3 Unknown NoneRPE65 1p31.2 RPE-specific 65-kd protein Recessive LCASAG 2q37.1 S-antigen; retina and pineal gland

(arrestin)Recessive Oguchi disease

TULP1 6p21.31 Tubby-like protein 1 Recessive LCAUSH2A 1q41 Usher syndrome 2A Recessive Usher syndrome

(continued)





RP genes, and numerous inexpen-sive,high-throughput techniquesex-ist for detecting these variants. 50,51

Second, another 20% of muta-tions were novel and could only bedetected by sequencing entiregenes.Further, each novel mutation re-quires careful evaluation of patho-genicity.Asa consequence, themain

bottleneck in genetic testing of pa-tients with RP is the need to screenand analyze many genes by expen-sive, time-consuming methods.For-tunately, promising high-through-put resequencing techniques, suchas microarray gene chips, may re-lieve this bottleneck. 52 Nonethe-less, interpretation of novel, rarevariants will still require profes-sional evaluation. 47

Third, some families thought tohave adRP actually have digenic orX-linked mutations. Digenic RP is

the result of 1 mutation in RDS anda second in ROM1.53 Different indi-vidual mutations in RDSand ROM1can cause adRP, but each of the di-genic mutations alone is not patho-genic. Digenic and polygenic inher-itanceis true ofother formsof retinaldisease, such as Bardet-Biedl syn-drome, which can be “triallelic.” 9

Another misleading mode of inher-itance among families diagnosedwith “adRP” is X-linked inherit-ance of RPGR mutations with sig-nificant disease in carrier fe-

males.44-46

Bothof these phenomenaare important reminders that themolecular diagnosis can radicallychange genetic counseling.

Fourth, at least 2.5%ofadRPmu-tations are genomic rearrangementsor deletions in PRPF31 that are notdetectable by conventional screen-ingmethods. 24 Whether therearedis-ease-causingdeletionsin other adRPgenes or in recessive or X-linkedgenes is an active area of research.This is likely, though, because dele-tions area commoncause ofother in-

herited andacquireddiseases.54-56

Forexample, large deletionscause up to17% of familial breast cancer. 57

The existence of disease-causingdeletions has significant implica-tions for molecular testing of pa-tients with RP. For one, routine test-ingmethods maymiss deletions (eg,sequencingdoes notdetect thebreastcancer deletions). For another, dele-tions may explain reported anoma-

lies in the frequencyandsegregationofRPmutations. If so, here again, themolecular diagnosiswillaffect coun-seling. Finally, this finding suggeststhat there may beother subtle muta-tions in known RP genes that aremissed by standard methods.

Fifth, there are definitely addi-tional, unknown adRP genes. Wefailed to detect mutations in 40% of the familieswe tested. Some,butnotall, of the remainingmutationsmay

be deletions or subtle changes inknown genes that have not been de-tected to date. 58 Linkage mappingcontinues to locate new adRPgenes—most recently RP31 andRP33.59,60 Likewise, new recessiveand X-linked genes are reportedregularly. 1

It is impossible topredictwhetherthere are several or many more RPgenes that have yet to be discov-

ered. Completion of the HumanGenome Project, newhigh-through-put screening methods, and devel-opment of powerful bioinformaticapproaches have dramatically re-ducedthetimeitwilltaketofindnewgenes. In spite of these technicalad-vances, the need for thorough,knowledgeable, innovative clinicalcharacterization ofpatients andfami-lies has never been greater.

RELEVANCE TO CLINICALPRACTICE AND FUTUREDIRECTIONS

What does thecurrent stateofRP ge-netics say of the future? A reason-able hope is that within 5 years, mo-lecular testing of newly diagnosedpatientswithRPwillbea routine partof clinical practice and will uncoverthe underlying disease-causing mu-

Table 2. Genes and Mapped Loci Causing Nonsyndromic, NonsystemicRetinitis Pigmentosa * (cont)

Symbol Location Protein Other Diseases

Autosomal Recessive LCAAIPL1 17p13.2 Arylhydrocarbon-interacting

receptor protein-like 1Dominant CORD

CEP290 12q21.32 Centrosomal 290-kd protein Recessive Senior-Lokensyndrome, recessiveJoubert syndrome

CRB1 1q31.3 Crumbs homolog 1 Recessive RPCRX 19q13.32 Cone-rod homeobox Dominant CORD, dominant

LCA, dominant RPGUCY2D 17p13.1 Guanylate cyclase 2D, membrane

(retina-specific)Dominant CORD

LRAT 4q32.1 Lecithin retinol acyltransferase Recessive RPLCA3 14q24 Unknown NoneLCA5 6q11-q16 Unknown NoneLCA9 1p36 Unknown NoneRDH12 14q24.1 Retinol dehydrogenase 12 NoneRPE65 1p31.2 RPE-specific 65-kd protein Recessive RPRPGRIP1 14q11.2 RP GTPase regulator interacting

protein 1None

TULP1 6p21.31 Tubby-like protein 1 Recessive RP

Autosomal Dominant LCACRX 19q13.32 Cone-rod homeobox Dominant CORD, recessive

LCA, dominant RPIMPDH1 7q32.1 IMP (inosine monophosphate)

dehydrogenase 1Dominant RP

X-Linked RPRP2 Xp11.23 RP-2 protein NoneRP6 Xp21.3-p21.2 Unknown NoneRP23 Xp22 Unknown NoneRP24 Xq26-q27 Unknown NoneRP34 Xq28-qter Unknown NoneRPGR Xp11.4 RP GTPase regulator X-linked COD, X-linked CSNB

Abbreviations: ATP, adenosine triphosphate; cGMP, cyclic guanosine monophosphate; COD, conedystrophy; CORD, cone-rod dystrophy; CSNB, congenital stationary night blindness; GTPase, guanosinetriphosphatase; LCA, Leber congenital amaurosis; MD, macular dystrophy; mRNA, messenger RNA;RP, retinitis pigmentosa; RPE, retinal pigment epithelium.

* References are in RetNet (http://www.sph.uth.tmc.edu/RetNet/).





tation (or mutations) in at least 90%of cases. For this hope to come true,4 conditions must be met:

1. Most of the genes causing RPmust be identified.

2. It must be possible to detectnearlyallof thedisease-causingmu-tations within these genes.

3. Mutation testing must be-come inexpensive, reliable, andwidely available.

4. We must be able to under-stand, interpret, andexplain themo-lecular information.

Before addressing these neces-sary conditions, it is worth askingwhyfinding the underlying disease-causing mutation should matter tothepatientor theclinician.Afterall,RP is currently an untreatable con-dition, sowouldn’t themolecular in-formation be of no use?

There are several compelling rea-sons whymolecular testing is impor-tant for clinical care. For one, iden-tifying the underlying mutation(s)can establish the diagnosis, whichmay be problematic otherwise. Thisis particularly important for child-hood retinopathies wherein the mo-lecular diagnosis may portend dis-

tinctlydifferentclinicaloutcomes.33,61

Also,knowing thegenetic cause ises-sential for familycounseling and forpredicting recurrencerisk andprog-nosis. In addition, each new muta-tionthat isfound contributesto a bet-ter understandingof ocular biology.Finally and of the most importance,theeraofgene-specific andmutation-specifictreatments for inheritedreti-nal diseases is quickly approach-ing. 62,63 Knowing the underlyinggenetic causewill beessentialfor en-rolling patients inclinical trials,a few

of which have begun already or willbegin shortly. 64,65 It is a safe predic-tion that in thenear future, there willbemany more treatmentandpreven-tion strategies based on knowledgeof the underlying mutation(s) in af-fected individuals and families.

Then, how close are we to rou-tine molecular diagnosis of RP?Identification ofnewRP genesis pro-ceeding swiftly. An educated guess(at best) is that most of the majorgenes, at least in Americans of Eu-ropean origin and Europeans, will

be found within 5 to 10 years. Whether current screening meth-ods, such as sequencing or micro-array testing, can detect all or evenmost of the mutations in knowngenes isdebatable. Not all of thegeneregions that could harbor muta-tions are tested routinely. For ex-ample, large intervening sequencesand noncoding regulatory regionsare usually ignored. Also, currentmethods do not detect large dele-tions or rearrangements. Ventur-inganother educated guess, though,

existing methods and methods un-der development will be able to de-tect most mutations, ie, more than90%, within 5 years.

Currently, the greatest road-block to molecular diagnosis of RPis the availability of genetic testing.Large commercial interestshave notyet entered the field, primarily be-cause there are somanygenes to testand so many inherent complica-

Table 3. Mutations in Genes That Cause an Appreciable Fraction of RetinitisPigmentosa Cases

Symbol% of All Cases

in Disease Category Source

Autosomal Dominant RPCRX 1.0 Sullivan et al,23 2006IMPDH1 2.5 Sullivan et al,23 2006PRPF3 1.0 Sullivan et al,23 2006

PRPF8 3.0 Sullivan et al,23

2006PRPF31 8.0 Sullivan et al,23 2006;Sullivan et al,24 2006

RDS 9.5* Sullivan et al,23 2006RHO 26.5 Sullivan et al,23 2006RP1 3.5 Sullivan et al,23 2006RPGR 1.0 Sullivan et al,23 2006Total 56.0

Autosomal Recessive RPABCA4 2.9 Klevering et al,25 2004CNGA1 2.3 Dryja et al,26 1995CRB1 6.5† Bernal et al,27 2003CRX 1.0 Rivolta et al,28 2001PDE6A 4.0 Dryja et al,29 1999PDE6B 4.0 McLaughlin et al,30 1995RPE65 2.0 Morimura et al,31 1998

USH2A 10.0 Seyedahmadi et al,32 2004Total 32.7

Autosomal Recessive LCAAIPL1 3.4 Hanein et al,33 2004CEP290 21.0 den Hollander et al,34 2006CRB1 10.0 Hanein et al,33 2004GUCY2D 21.2 Hanein et al,33 2004RDH12 4.1 Perrault et al,35 2004RPE65 6.1 Hanein et al,33 2004RPGRIP1 4.5 Hanein et al,33 2004TULP1 1.7 Hanein et al,33 2004Total 72.0

Autosomal Dominant LCACRX 1 Perrault et al,36 2003;

Sohocki et al,37 1998

IMPDH1

1 Bowne et al,11

2006Total Unknown

X-Linked RPRP2 15.1 Pelletier et al,38 2006RPGR 74.2 Pelletier et al,38 2006‡Total 89.3

Abbreviations: adRP, autosomal dominant retinitis pigmentosa; LCA, Leber congenital amaurosis;RP, retinitis pigmentosa.

* Includes 1 family with digenic RDS -ROM1 mutations.†Up to 50% of recessive RP with Coats disease or para-arteriolar preservation of the retinal pigment

epithelium.39

‡Includes families with X-linked retinitis pigmentosa not linked to RP2 or RPGR .





tions. However, methods for rapid,inexpensivedetection of known RPmutations exist today and will beroutinely available soon. 51,66 Also,targeted screeningofgenesandgeneregions that are frequent causes of inheritedretinal diseases is being of-fered on a fee-for-service basis by afewinstitutions in theUnitedStates

andEurope (see theGeneTestsWebsite for further information 67).Inad-dition, theNationalEye Institutehasrecently developed a program,eyeGENE TM,68 to facilitate genetictesting of inheritedeyediseases. Fi-nally, it is reasonable to expect thatnew high-throughput sequencingmethods will makegenetic testing of all diseases affordable and efficientwithin 10 years. 69

In our op in ion , the majorimpediment to routine moleculardiagnosis of RP is not technical or

commercial but rather informa-tional. No aspect of understanding,interpreting, and explaining themolecular causes of RP is routine.Skilled, informed clinical diagnosismust precede testing. Even if genetic testing is standardized,interpretation of novel variants willrequire sophisticated analysis.Understanding the resul ts of genetic testing will be challenging,especially if novel findings such aspolygenic inheritance are involved.Making sense of this to patients

and families in a helpful and sup-portive way will require good coun-seling skills. Finally, when gene-specific and mutation-specifictreatments become available, whichis inevitable, even greater levels of knowledge and understanding willbe demanded.

Noneofthis isunique toRP: mo-lecular diagnostics will enrich allas-pects ofmedical care in future years. What is unusual, though, is the ex-tent of thecurrent knowledge of themolecular causes of inherited reti-

nal diseases and the recognition of the underlying complexity. Thus,clinical ophthalmology has theunique opportunity to prepare forthe near future by enhancing train-ing in genetics, incorporating ge-netic counseling at all levels of care,and developing specialized centersfor thediagnosis andtreatmentof in-herited eye diseases. Another rea-sonable prediction is that the oph-

thalmology profession will lead theway for otherbranchesof medicine.

Submitted for Publication: Septem-ber 14, 2006; final revision re-ceived September 29, 2006; ac-cepted October 2, 2006.Correspondence: StephenP. Daiger,PhD, Human Genetics Center,

School of Public Health, 1200 Her-man Pressler Dr, The University of Texas Health ScienceCenter,Hous-ton, TX 77030-3900 ([email protected]).Financial Disclosure: None re-ported.Funding/Support: This study wassupported by grants from theFoun-dation Fighting Blindness, the Wil-liamStamps Farish Foundation, theGustavus and Louise Pfeiffer Re-search Foundation, and the Her-mann Eye Fund as well as by grants

EY007142 and EY014170 from theNational Institutes of Health.

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