Survey of Ophthalmology
Volume 49, Issue 2 , Pages 159-196, March 2004

Ocular genetics: current understanding☆

  • Ian M MacDonald, MSc, MD CM

      Affiliations

    • Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada
    • Corresponding Author InformationReprint address: Ian M. MacDonald, MD CM, Ocular Genetics Laboratory, University of Alberta, 832 Medical Sciences Bldg., Edmonton, AB Canada T6G 2H7.
    • ,
  • Mai Tran, BSc

      Affiliations

    • Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada
    • ,
  • Maria A Musarella, MD

      Affiliations

    • Long Island College Hospital, Department of Ophthalmology, Brooklyn, New York, USA
    • SUNY Downstate Medical Center of Brooklyn, Department of Ophthalmology, Brooklyn, New York, USA

Article Outline

Abstract 

Over the past decade, there has been an exponential increase in our knowledge of heritable eye conditions. Coincidentally, our ability to provide accurate genetic diagnoses has allowed appropriate counseling to patients and families. A summary of our current understanding of ocular genetics will prove useful to clinicians, researchers, and students as an introduction to the subject.

Keywords:  genetic counseling, molecular genetics, ocular genetics

 

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I. Introduction 

More than 10 years have passed since the Survey of Ophthalmology last reviewed ocular genetics.288 The pace of gene discovery has since increased significantly as we now use technologies and the Human Genome Project databases which were not previously available. The contribution of ocular genetics to human discovery has been exceptional, beginning with a strong interest in ocular genetics by many clinical ophthalmologists who carefully described the patterns of inheritance of familial eye disorders. Families readily participated in research to understand the nature of their illness with the hope that new treatments might be found to prevent blindness. A specific clinical and genetic diagnosis provides the patient and family with a framework for discussions on prognosis, treatment, and the heritability of a condition. As genotyping of specific conditions is possible in research and clinical laboratories, we are beginning to consider targeting specific therapies for these conditions. Clinical trials for these conditions will need to emerge in the future to study the effect of these treatments.

An up-to-date summary of the present state of ocular genetics was deemed important. This review has limited its scope to human conditions and syndromes that primarily affect the eye with the intent of being comprehensive but not exhaustive. Some conditions, especially metabolic disorders affecting the eye, have not been included; whereas some multisystem disorders have been included to allow a more complete discussion of ocular genetics. Although the disorders are presented in the traditional manner according to their phenotype, we are increasingly aware that mutations in the same gene may result in disparate phenotypes.

The original strategies of gene discovery used linkage analysis with molecular genetic tools to first define the locus of a particular gene, as in the case of X-linked retinitis pigmentosa.48 Physical mapping then refined the map location of the gene to an area from which a gene could be cloned. This approach has generally been defined as positional cloning. As the resources of cloned segments and map locations increased, an alternate approach, candidate gene analysis, was used successfully in some cases. If the map location was defined, a search of databases could reveal a gene mapped to the same location that potentially was involved in the pathophysiology of the condition. Autosomal dominant RP (adRP) was linked to the same locus as the gene for rhodopsin (RHO), and mutations were subsequently discovered in RHO in patients with adRP.106 Our knowledge of other mammalian genomes has been additive in the search for genes underlying human conditions. For example, cloning the mouse pink-eye dilution gene, p, enabled the discovery of the human homologue, P, that is mutated in tyrosinase positive oculocutaneous albinism.140 Similary, cloning the brown (b) gene in mouse allowed Boissy and coworkers to identify mutations in the TYRP-1 gene in brown oculocutaneous albinism.55

In the table of heritable eye conditions accompanying this review (Table 1), we have listed the disorders by their phenotype. Where possible, the gene (or symbol used to denote the gene) which is mutated, and the protein encoded by that gene have been verified according to the nomenclature proposed by the Human Gene Nomenclature Database. The exceptional resources of Online Mendelian Inheritance in Man (OMIM™) and the Retinal Information Network (RetNet™) will continue to provide upto-date knowledge of specific conditions. There is currently no clearinghouse for clinicians who are interested in pursuing the genetics of a heritable condition in a patient or family. GeneTests does, however, act as a resource to link clinicians with diagnostic and research laboratories for some of these conditions.

Table 1. Heritable Eye Disorders
Gene/SymbolProteinLocusReferences
Anterior Segment Conditions
AniridiaPAX6Paired box transcription factor 611p13392
Axenfeld-Rieger anomalyFOXC1Forkhead box C1 transcription factor6p25266., 307.
Axenfeld-Rieger syndromePITX2Paired-like homeodomain transcription factor 24q25360
Axenfeld-Rieger syndromeRIEG2 13q14325
Axenfeld-Rieger syndrome 16q24
Iridogoniodysgenesis anomaly (iris hypoplasia)FOXC1Forkhead box C1 transcription factor6p25228., 229.
Iridogoniodysgenesis syndromePITX2Paired-like homeodomain transcription factor 24q2512., 226.
Peters anomalyPAX6Paired box transcription factor 611p13159
Peters anomalyPITX2Paired-like homeodomain transcription factor 24q25100
Corneal Dystrophies
Avellino corneal dystrophyβig-h3Kerato- epithelin5q31285
Granular corneal dystrophy (Groenouw type I)βig-h3Kerato-epithelin5q31285
Lattice type I corneal dystrophyβig-h3Kerato-epithelin5q31285
Meesman dystrophyKRT3 KRT12Keratin 3 Keratin 1217q12178
Reis-Bücklers corneal dystrophyβig-h3Kerato-epithelin5q31285
Lens disorders
AculeiformCRYGDCrystallin, gamma D2q33-q35164
Anterior Polar Type I (CTAA1) 14q24-qter128., 272.
Anterior Polar Type II (CTAA2) 17p1344
Posterior Polar 1pter-p36.1177
Posterior PolarCRYABCrystallin, alpha B11q22-q22.343
Cerulean Type I (CCA1) 17q2421
Cerulean Type II (CCA2)CRYBB2Crystallin, beta B222q11.2-12.2221., 233.
Lamellar Zonular pulverulent (CZP1) (Coppock)GJA8Connexin 501q21.1368
Coppock-like (CCL)CRYBB2Crystallin, beta B222q11.2-12.2145
Coppock-like (CCL)CRYGCCrystallin, gamma C2q33-q35164., 237.
Congenital cataract (ad)PITX3Paired-like homeodomain transcription factor 310q25361
Congenital cataract (ad)MIPMajor intrinsic protein12cen-q14130
Congenital cataract (ar)CRYAACrystallin, alpha A21q22.3329
Marner type (CAM) 16q22.1110
Volkmann type 1pter-1p36.13109., 172.
Dominant pulverulentCRYBB1Crystallin, beta B1 247
Dominant zonular pulverulent (CZP3)GJA3Connexin 4613q11-q12335
Nonnuclear polymorphic congenital (ad) 2q33-q35344
Zonular with sutural opacities (CCZS)CRYBA1Crystallin, beta A117q11-q12314
Glaucoma
Normal tension glaucomaOPTNOptineurin10p13336
Primary open angle, aggressive (GLC1A)MYOCMyocilin1q21-2338., 384.
POAG (moderate tension) (GLC1B) 2cen-q13381
POAG (high tension) (GLC1C) 3q21-q24419
POAG (moderate tension) (GLC1D) 8q23393
POAG (normal tension) (GLC1E) 10p14-p15351
POAG (GLCIF) 7q35420
Primary congenital (GLC3B)CYP1B1Cytochrome P450, subfamily, polypeptide 12p21350
Primary congenital 1p367
Pigment dispersion 7q35-q3615
Pigment dispersion 18q11-q2114
Vitreo-retinal Disorders
Erosive vitreo-retinopathy 5q13-q1466
Familial exudative vitreo-retinopathy, (ad)FZD4Frizzled protein 411q14-q21343
Familial exudative vitreo-retinopathy, (x1)NDPNorrinXp11.342., 78.
Norrie diseaseNDPNorrinXp11.342., 78.
RetinoschisisRS1RetinoschisinXp22.2352
Wagner disease 5q14.366., 322.
Albinism
OCA Type IATYRTyrosinase11q14-2125
OCA Yellow – IBTYRTyrosinase11q14-2125
OCA Temperature- sensitive – I-TSTYRTyrosinase11q14-2125
OCA Type IIP 15q11.2-q12141., 334.
OCA Brown (Type III)B, TYRP-1Tyrosinase-related protein9p2355
OCA Type IVHuman orthologue of underwhiteMembrane- associated transport protein5p302
OcularOA1Novel proteinXp22.327
Color Vision Defects
Achromatopsia (Pingelapese)CNGB3Cone cyclic nucleotide-gated cation channel beta 38q21-q22387., 418.
AchromatopsiaGNAT2Cone specific alpha subunit of transducin1p13217
Incomplete achromatopsiaCNGA3Cyclic nucleotide gated channel alpha 32q11.2422
Rod monochromacyCNGA3Cyclic nucleotide gated channel alpha 32q11.219., 422.
Rod monochromacy 14320
Blue cone monochromacyBCM Xq28, multiple mutations and deletions of red/green cluster230
DeuteranopiaOPN1MWGreen cone pigmentXq28298
ProtanopiaOPN1LWRed cone pigmentXq28298
TritanopiaOPN1SWBlue cone pigment7q31.3-q32414
Autosomal Dominant Retinitis Pigmentosa
RP18 1q13-q23427
RP4RHORhodopsin3q21-q24104
RP7RDSPeripherin6p21.2-cen105., 194.
Retinitis punctata albescensRDSPeripherin6p21.1-cen195
RP9 7p13-p15176
RP10IMPDH1Inosine mono-phosphate dehydrogenase 17q31.360., 277.
RP1ORP1Oxygen- regulated photoreceptor protein 18q11-q13181
NRLNeural retina leucine zipper14q11.246
RP13PRPF8Pre-mRNA processing factor 817p13.3149., 262.
RP17 17q224
FSCN2Retinal fascin17q25401
RP11PRPF31Pre-mRNA processing factor 3119q13.48., 398.
Autosomal Recessive Retinitis Pigmentosa
RP19ABCA4ATP binding cassette transporter1p22254
RP12 (with para-arteriolar preservation of RPE); RP with Coat's like vasculopathyCRB1Crumbs homolog 11q31-q32.195., 96.
RP28 2p11-p16153
MERTKc-mer proto- oncogene tyrosine kinase2q14.1136
RP26 2q31-q3332
Retinal degenerationPROML1Prominin-like 14p259
PDE6BRod cGMP phosphodiesterase, beta4p16.331
(rod)CNGA1Cyclic nucleotide gated channel alpha 14p12-cen103
Severe early onsetLRATLecithin retinol acyltransferase4q31.259
RP29 4q32-q34316
PDE6ARod cGMP phosphodiesterase, alpha5q31.1-q34174
RP14TULP1Tubby-like protein 16p21.3156
RP25 6cen-q15208
RGRRetinal G protein coupled receptor10q2376., 281.
RPE degenerationRBP4Retinol binding protein 410q24359
arRP including Enhanced S-cone syndromeNR2E3Nuclear receptor15q23142., 157.
RP22 16p12.1-p12.3123
Autosomal Recessive Retinal Degeneration
Bietti crystalline corneoretinopathy 4q35-tel185
Fundus albipunctatusRDH5Retinol dehydrogenase 512q13-q1483., 428.
Retinitis punctata albescensRLBP1Retinaldehyde binding protein 115q2669
X-linked Retinitis Pigmentosa
RP23 Xp22161
RP6 Xp21.264
RP3, RP15RPGRRP GTPase regulatorXp21.1265., 289., 290., 397.
RP2 Novel proteinXp11.348., 160.
RP24 Xq26-27144
Digenic RPRDS/ROM1Peripherin/rod outer segment protein-16p21.2;11q13105
ChoroideremiaCHMRab escort protein 1Xq21.1-q22.389
Usher syndrome
USH1A (French) 14q32199
USH1BMYO7AMyosin VIIA11q13.5410
USH1C Harmonin11p15.1416
USH1DCDH23Cadherin related adhesion protein 2310q21-q2256., 58., 182., 186.
USH1E 21q2175
USH1FPCDH15Protocadherin 1510q21-226
USH2A Usherin1q41416
USH2B 3p24.2-p23167
USH2C 5q14-q21326
USH3A Novel protein3q21-q2595., 186.
Leber Congenital Amaurosis
LCA1GUCY2DRetinal guanylate cyclase 2D17p13.171
LCA2(RP20)RPE65RPE-specific protein1p31154., 236., 281.
LCA3 14q24379
LCA4AIPL1Aryl hydrocarbon receptor interacting protein-like 117p13.1374
LCA5 6q11-q1697
LCA6RPGRIP1RP GTPase regulator interacting protein 114q11102
CRB1Crumbs homolog 11q31235
CRXots-like photoreceptor- expressed homeobox transcription factor19q13.3388
Bardet-Beidl Syndrome
BBS1 11q1333
BBS2 16q2133
BBS3 3p13-p1233., 433.
BBS4 15q22.3-q2333
BBS5 2q31426., 431.
BBS6MKKSPutative chaperonin20p12201., 383.
Systemic Forms of RP
infantile Refsum disease (ar)PEX1Peroxisome biogenesis factor 17q21-q22328
Refsum disease (ar)PHYHPhytanolyl- CoA hydroxylase10p15.3-p12.2183., 271.
Kearns-Sayre Syndrome; chronic progressive external ophthalmoplegiaKSSATPase subunit 6Mitochondrial DNA, deletions280
Neuropathy, ataxia and RP ATPase subunit 6Mitochondrial DNA, 8993 point mutation169
RP with progressive sensorineual hearing lossMTTS2tRNA serine 2Mitochondrial DNA, 12258 point mutation251
RP and ataxiaTTPAAlpha- tocopherol transfer protein8q13-q13.3429
Congenital Stationary Night Blindness
adGNAT1Rod transducin, alpha subunit3p21104
adPDE6BRod cGMP phosphodiesterase, beta4p16.3137
Oguchi disease (ar)SAGArrestin (S-antigen)2q37.1135
Oguchi disease (ar)RHOKRhodopsin kinase13q3483
CSNB1 (xl)NYXNyctalopinXp11.4-p11.336
CSNB2 (xl)CACNA1FL-type voltage-gated calcium channel, alpha 1F subunitXp11.2337
Macular Dystrophy
Best vitelliform dystrophyVMD2Bestrophin11q13324., 386.
Doyne honeycomb retinal dystrophyEFEMP1EGF-containing fibulin-like extracellular matrix protein 12p16385
Macular dystrophy; pseudovitelliformRDSPeripherin6p21.2121., 218.
North Carolina macular dystrophyMCDR1 6q14-q16.2373
Sorsby fundus dystrophyTIMP3Tissue inhibitor of metalloproteinase 322q12.2-q13.218
Stargardt macular dystrophy (ar) (STGD1)ABCA4ATP binding cassette transporter1p2210
Stargardt-like macular dystrophy (ad) (STGD3)ELOVL4Elongation of very long chain fatty acids 46q14434
STGD4 (ad) 4p215
Retinoblastoma
RB1Tumor suppressor13q14.274
Gyrate Atrophy
OATOrnithine aminotransferase10q26393., 394.
Cone Dystrophy
COD1 (xl) Xp11.4362
COD2 (xl) Xq2741
COD3 (ad)GUCA1AGuanylate cyclase activator-1A6p21.1317
Cone Rod (CORD) Dystrophies
CORD1 18q21.1-q21.3406
CORD2CRXots-like photoreceptor- expessed homeobox transcription factor19q13.3132
CORD3ABCA4ATP binding cassette transporter1p2288
CORD5 17p13-p1223
CORD6GUCY2DRetinal guanylate cyclase 2D17p13.1202., 204.
CORD7 6cen-q14203
Optic Nerve
Optic atrophy (Kjer)OPA1Mitochondrial dynamin-related protein3q28-q2910., 93., 108.
Dominant optic atrophy 18q13.2-q12.3206
Optic nerve colobomas (oculorenal syndrome)PAX2Paired box protein 210q2513., 118.
Leber hereditary optic neuropathyLHONComplex, I, III, IV of respiratory chainMitochondrial DNA, several point mutations175
Disorders of the Lids and Ocular Adnexae
Blepharophimosis, ptosis, epicanthus inversus with premature ovarian failure (BPES type I)FOXL2Forkhead box L2 transcription factor3q2390
BPES without ovarian failure (BPES type II)FOXL2Forkhead box L2 transcription factor3q2390
Ptosis (ad) 1p32-p34.1113
Ptosis (xl) Xq24-q27.1264
Anophthalmia/Micro-ophthalmia
Anophthalmia Xq27-q28151
Micro-ophthalmia (ad) 15q12-q15283
Micro-ophthalmia (ar) 14q3245
Nanophthalmia (microphthalmia) (ad) 11p313
Disorders of Ocular Motility
Congenital fibrosis of extraocular muscles, type 1 (FEOM1) 12p12.1-q13.2112
FEOM2 (ar)ARIX (PHOX2A)Homeodomain transcription factor11q13.2295
FEOM3 16q24.2-q24.399., 248.
Congenital oculomotor apraxia 2p1347
Duane's retraction syndrome Type 1 (DURS1) 8q1370
DURS2 2q3117., 116.
Nystagmus, congenital motor 1 (NYS1)(xl) Xq26-q27207
NYS2 (ad)NYS2 6p12205
Refractive Errors
Myopia 3 (MYP3)(ad) 12q21-q23432
MYP2 (ad) 18p11.31430
MYP1 (xl) Xq28356

ad=autosomal dominant; ar=autosomal recessive; xl=X-linked.

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II. Anterior segment conditions 

A. Aniridia 

Aniridia is a rare disorder that causes corneal pannus, cataracts, glaucoma, partial or complete absence of the iris, and foveal hypoplasia (Fig. 1).365 The degree of visual impairment is quite variable and the phenotype of aniridia can include cases of autosomal dominant keratitis.275 Differences in the degree to which the anterior segment is affected by pannus, iris hypoplasia, and cataracts can be observed between related affected individuals and within individuals.241

Aniridia can be inherited as an autosomal dominant trait or occur sporadically, without a previous family history, presumably due to a new mutation or non-paternity. One-third of sporadic cases of aniridia develop Wilms tumor. A sporadic case of aniridia warrants investigation with abdominal ultrasound examination to rule out the possibility of Wilms tumor.166 Riccardi and coworkers described several cases of aniridia and Wilms tumor associated with an interstitial 11p deletion and proposed a contiguous gene syndrome (WAGR=Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) due to genes in the region.337 If a sporadic case of aniridia exhibits multiple congenital anomalies (especially genitourinary anomalies), karyotypic analysis is appropriate. The syndromic form of aniridia (WAGR) results from deletion of the contiguous genes: PAX6 and the Wilms tumor suppressor gene 1 (WT1).319

The gene for aniridia, PAX6, was cloned by Ton et al.392 The PAX (paired box) genes were identified and so designated because of sequence homology to the Drosophila segmentation genes, paired and gooseberry.68 To date nine members of this gene family have been identified in humans and are designated PAX1 through PAX9.348 All cases of familial aniridia result from a mutation in one copy of the PAX6 gene creating haploinsufficiency of the gene product.146 For patients with a clear history of dominantly inherited aniridia, further investigations are generally unnecessary.

B. Axenfeld-Rieger malformation 

Abnormal migration of neural crest cells and their derivative structures are presumed to cause anomalous formation of the anterior segment of the eye.34., 187. During the sixth week of embryonic life, neural crest cells migrate to form the corneal endothelium, the iris stoma, and the trabecular meshwork.22., 187. Differentiation of neural crest cells and a cascade of transcription factors are involved in normal anterior segment morphogenesis. The pathogenesis of several anterior segment disorders: iris hypoplasia or iridogoniodysgenesis, posterior polymorphous corneal dystrophy, and Axenfeld-Rieger malformation may then be linked to defects in these genes.

Although traditional teaching has separated anterior segment malformations into those limited to the eye and those including systemic features, the genetics of these disorders suggests that mutations in a few genes may cause overlapping phenotypes. The Axenfeld-Rieger malformation comprises Axenfeld-Rieger anomaly (ARA) and Axenfeld-Rieger syndrome (ARS). ARA has findings limited to the eye, including a malformed anterior chamber and prominent, anteriorly displaced Schwalbe's line (Fig. 2).189 ARS has added systemic features including dental anomalies, failure of involution of the periumbilical skin (umbilical hernia), mild craniofacial dysmorphism, and, less frequently, hydrocephalus and hearing, cardiac, kidney, and limb defects.81., 119., 126., 249. Both ARA and ARS behave as autosomal dominantly inherited traits. Fifty percent of individuals with AR malformation develop glaucoma usually in childhood or young adulthood.367

Linkage analysis of families with ARA localized a locus to chromosome 6p25.150 Mutations in the forkhead-like 7 gene, FOXC1 which mapped to 6p25, were independently identified in families with ARA by Mears et al266 and Nishimura et al.307 Not surprisingly, a mutation in this gene was later found in ARS.273 Further, duplications of this gene have been found in iris hypoplasia with glaucoma (iridogoniodysgenesis)229 and in the AR malformation.306

Murray and coworkers first established linkage of a locus for ARS (RIEG1) to chromosome 4q25.286 Later characterization of the RIEG1 gene identified it as the homeobox transcription factor, PITX2.360 Members of the homeobox transcription gene family have roles in genetic control of development, especially in the specification of the body plan, pattern formation, and determination of cell fate.222 The spectrum of phenotypes iris hypoplasia, iridogoniodysgenesis syndrome (IDGS), and ARS is likely due to the amount of residual PITX2 activity in patients with mutations in this gene.220 Phillips et al localized a second ARS locus, RIEG2, to chromosome 13q14 through linkage studies.325 A third putative locus at 16q24 for AR malformation has been inferred through the studies of cases with chromosomal anomalies.122., 415.

Iridogoniodysgenesis or iris hypoplasia is part of the spectrum of Axenfeld-Reiger malformation. Iridogoniodysgenesis (IGD) was first described by Berg in 1932,40 as maldevelopment of the trabecular meshwork and iris. The pigmented iris epithelium is seen through a hypoplastic anterior iris stroma resulting in a peculiar eye color (slate gray or chocolate brown). The normal pupillary sphincter stands out as an elevated tan-colored ring against a rather featureless gray background (Fig. 3). Prominence of the pupillary sphincter may also be seen in the Axenfeld-Rieger malformation. Similar to the Axenfeld-Rieger malformation, two phenotypes have been described: IGD anomaly (IGDA) characterized by iris hypoplasia, goniodysgenesis, and juvenile glaucoma with no systemic findings; and IGD syndrome (IGDS) with additional nonocular features: dental and jaw anomalies. Both traits are inherited in an autosomal dominant fashion. Although phenotypic expression is variable, penetrance of the trait is high.184., 318., 407. The degree of iris and trabecular meshwork malformation does not correlate with either the development or the severity of glaucoma.318., 407. Glaucoma arises in between 75% and 100% of patients with IGD,150., 274., 286., 407. and is usually detected in the second decade of life.184

Iridogoniodysgenesis anomaly was originally mapped to chromosome 6p25 by Mears and colleagues.267 Duplication of FOXC1, which maps to 6p25, has been shown in families with iris hypoplasia (IGDA).228., 229. IGDS was mapped to chromosome 4q25, allelic to ARS, and was later shown to be due to mutations in PITX2.11., 226. The major genes involved in the AR malformation are therefore FOXC1 and PITX2. Mutations in these genes cause a spectrum of anterior segment phenotypes but within individual families the phenotypes tend to be specific.

C. Peters anomaly 

Peters anomaly is a congenital malformation of the anterior chamber of the eye resulting in corneal clouding and variable iridolenticular corneal adhesions.323., 382. Cases are usually sporadic in nature, but families have been described in whom the disorder is inherited as an autosomal dominant165., 168. or autosomal recessive trait.53 Mutations in PAX6 were first implicated in Peters anomaly by Holmstrom and colleagues.168 In 1994, Hanson et al reported that a deletion of one copy of PAX6 caused Peters anomaly.159 A mutation in PITX2 has also been demonstrated in a case of Peters anomaly.100 The patient's father, although not available for examination, was reported to have nystagmus, glaucoma, and poor dentition.

Other loci may also be involved in Peters anomaly as the disorder occurs occasionally with systemic features (Peters plus syndrome or Krause-Kivlin syndrome), hinting at the possibility of a contiguous gene syndrome or mutations in a single gene with phenotypic variability.163., 210., 211. Similar to cases of aniridia, Peters anomaly has been described in conjunction with Wilms tumor.111., 190. A renal ultrasound examination should be performed to rule out the presence of Wilms tumor. At least five chromosomal syndromes have been associated with Peters anomaly: deletions in chromosomes 4,260 11,30 and 18,147 ring chomosome 21,82 and a balanced translocation, t(2;15).211

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III. Corneal dystrophies 

A. βig-h3 

Skonier et al first isolated βig-h3, the human transforming growth factor beta-induced gene.371., 372. This gene maps to chromosome 5q31 and is transcribed almost exclusively in the corneal epithelium and stromal keratocytes.114 Using a candidate gene approach, Munier et al found that mutations in this gene cause four corneal disorders that map to 5q31: granular corneal dystrophy or Groenouw type I, Reis-Bücklers, lattice type I corneal dystrophy, and Avellino corneal dystrophy.285

These autosomal dominant disorders are characterized by progressive accumulation of corneal deposits beginning in the first or second decade of life. Granular corneal dystrophy and lattice corneal dystrophy are the most common inherited corneal dystrophies.285 There is considerable overlap between their clinical and histological characteristics.293 In granular corneal dystrophy, discrete white granular opacities first appear in the central superior region of the cornea.292 With time, the number of deposits increase, extend, and deepen, obscuring vision. These deposits have been referred to as “hyalin.” Lattice corneal dystrophy is classified as a single-organ amyloidosis. Branching linear amyloid deposits localize to the central cornea and gradually opacify the visual axis.213 Reis-Bücklers corneal dystrophy has been classified as a dystrophy of Bowman's layer and the superficial stroma. Early onset, painful recurrent corneal erosions, and more superficially localized corneal opacities distinguish it from granular corneal dystrophy.224 Avellino corneal dystrohy is considered a mixed dystrophy as it presents clinical characteristics similar to both granular and lattice corneal dystrophy.127

B. Meesmann dystrophy 

Meesmann corneal dystrophy (MCD) is an autosomal dominant disorder that affects only the corneal epithelium.124 Uniform, round intraepithelial cysts are usually visible by age 12 months and increase in number throughout life (Fig. 4). Rupture of these corneal microcysts in adulthood results in symptoms of photophobia, contact lens intolerance, and intermittent decreased visual acuity.

In 1997, Irvine et al mapped the keratin 12 gene (KRT12) to chromosome 17q12 and showed that dominant negative mutations in the keratin 3 gene (KRT3) and KRT12 encoding the cornea-specific keratins, K3 and K12, cause Meesmann corneal dystrophy.178 Corneal epithelial cells contain intermediate filament proteins, cytokeratins. During stages of epithelial differentiation, specific pairs of different keratin chains are coexpressed. The keratin pair K3 and K12 are coexpressed in the most anterior portion of the cornea epithelium.354

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IV. Lens disorders 

Ninety percent of the lens is composed of two types of protein: soluble (crystallin) and insoluble proteins (membrane and cytoskeletal proteins). There are three main families of crystallins. Alpha-crystallins appear to be molecular chaperones for the beta- and gamma-crystallins, helping them to fold properly as they are synthesized and aiding them in refolding if they denature.170 Beta-crystallins and gamma-crystallins have similar structures. Their tertiary structures have two domains that contain beta sheets and the entire proteins are compact and globular. The transparency of the lens depends on a highly structured arrangement of lens proteins and lens fibers.92 An elaborate system of gap junctions, formed by the connexins, allows access to metabolically inert cells within the lens. Crystallins, connexins, and developmental factors (PAX6, PITX3) may all be responsible for maintaining lens clarity.162 All the proteins that function in maintaining the clarity of the lens could be potential candidate genes causing heritable cataract.

The clinical descriptions of heritable cataracts have been adopted as an outline for this section. Significant genetic heterogeneity does exist however, and so phenotypes do not correlate uniquely with mutations in individual genes. Many factors both environmental and genetic contribute to the formation of a cataract.

A. Aculeiform cataract 

Aculeiform cataracts are inherited in an autosomal dominant fashion. Usually needle-like lens opacification occurs bilaterally. In 1999, Héon et al screened for mutations in the crystallins in three unrelated affected families.164 They found a G to A transition mutation in exon 2 of the crystallin gamma D gene (CRYGD), which substituted a histidine for the highly conserved arginine (R58H). The R58H mutation induces a change in charge, which introduces a hydrogen bond that subsequently impairs the proper folding of the protein by either increasing its rigidity or altering its stability. The mutation may also destabilize contact between lens fiber cells thereby affecting maintenance of lens transparency.

B. Polar cataracts 

1. Anterior polar cataract 1 (CTAA1) 

Anterior polar cataracts are characterized by variable dense, white opacities in the anterior lens. They may be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion.269 Independent studies support a locus for anterior polar cataracts on chromosome 14. In 1984, Moross et al described a family with a balanced translocation t(2;14)(p25;q24) and anterior polar cataract.284 In 1992, Miller et al found that the karyotype of an infant girl with multiple congenital anomalies and unilateral nuclear cataract was mosaic 46,XX/46,XX,del(14) (q32.3).272

Arrhythmogenic right ventricular dysplasia (ARVD), an autosomal dominant disorder, is a major cause of sudden death at a young age.39., 390. ARVD was mapped to 14q23-24 by Rampazzo et al.333 A locus for anterior polar cataract has been mapped adjacent at 14q24-qter.263 Frances et al reported a brother and sister who had both ARVD and anterior polar cataracts.128 Their parents were second cousins, but healthy.

2. Anterior polar cataract 2 (CTAA2) 

Berry et al reported a locus for autosomal dominant anterior polar cataract at 17p13 in a four-generation family.44

3. Posterior polar cataract 

In 1997, Ionides et al linked a locus for autosomal dominant posterior polar cataract to 1p in one family.177 In another four-generation family, a mutation in the crystallin alpha-B gene was found to segregate with autosomal dominant posterior polar cataract.43 The mutation likely affects posttranslational modification and protein folding.

C. Cerulean cataract 

Cerulean cataracts are characterized by variable coarse deposits that are mostly lamellar and manifest a combination of white, blue and purple hues. The phenotype is genetically heterogeneous, in that a mutation in more than one gene can cause a similar phenotype.

1. Cerulean cataract, type I (CCA1) 

Vogt first described cerulean cataract type I in 1922 as blue and white opacifications in a concentric pattern with occasional radially arranged lesions in the fetal nucleus.399 In 1995, Armitage et al linked a four-generation pedigree with cerulean cataract to chromosome 17q24.21 In this family, newborns did not have lens changes until the age of 18 to 24 months. The authors suggested that cerulean cataracts be classifed as developmental rather than congenital cataracts. Three possible candidate genes located in the region of 17q24: the DHP-sensitive calcium channel γ subunit (CACNLG), the human somatastatin receptor (SSTR2) and the skeletal muscle sodium channel α subunit (SCN4A0) were excluded by linkage analysis with intragenic DNA repeat polymorphisms. The galatokinase gene (GALK1) mapped to 17q23-25 was also excluded as a possible candidate gene.21 More recently, a population based study has suggested that mutations in GALK may predispose to adult cataract.311

2. Cerulean cataract, type II (CCA2) 

Cerulean cataract type II is an autosomal dominant form of congenital cataract. Young affected individuals have many blue flakes in the peripheral lens and some spoke-like opacities in the central lens. In 1996, Kramer et al reported linkage of CCA2 to the beta cystallin locus by studying a family originally reported by Bodker et al.52., 221. The daughter of two affected first cousins was born with congenital bilateral microphthalmos and microcornea. She was homozygous for the disease-bearing chromosome. Curiously one individual in the family carried the disease chromosome, but was unaffected. In 1997, Litt et al found a chain-terminating mutation in the crystallin beta B2 (CRYBB2) gene in this family.233 Héon and coworkers found the same mutation in a family with the Coppock-like cataract phenotype.145

D. Coppock and Coppock-like cataract 

1. Lamellar zonular pulverulent cataract (Coppock) (CZP1) 

The Coppock cataract was the first inherited disorder to be linked to an autosome.85 Dominant lamellar zonular pulverulent cataract or Coppock cataract (CZP1) is characterized by opacities in both the embryonic nucleus and the fetal nucleus. The CZP1 cataract measures about 4 mm in comparison to the Coppock-like cataract that measures about 2 mm. Shiels et al found that CZP1 mapped to the same locus as the GJA8 gene (connexin50).368 A C to T missense mutation was found in codon 88 of GJA8 that substituted a phylogenetically conserved proline for a serine (P88S).

2. Coppock-like cataract (CCL) 

Coppock-like cataract is inherited in an autosomal dominant fashion and is also genetically heterogeneous. Clinically, it appears as a dustlike opacity of the fetal nucleus with frequent involvement of the zonular lens. In one family, mutation analysis of exon 2 of the crystallin gamma C gene (CRYGC) by Héon et al revealed in an A to a C transversion, changing the amino acid threonine to a proline (T5P) in a highly conserved region.164 The change hypothetically disturbs protein function and/or the protein's interaction with neighboring proteins, as proline is known as a potent breaker of β-sheets. Impaired folding of the protein likely leads to lens opacification.

E. Marner type cataract (CAM) 

In 1949, Marner described a family with 132 affected members in eight generations.253 Affected individuals presented with zonular cataract although some had nuclear, anterior polar, or stellate cataract. The disorder was progressive and anticipation was suggested (the trait appears to worsen with each generation). In 1988, Eiberg et al linked the disorder to the locus for haptoglobin on chromosome 16 in the family originally studied by Marner.110 Richards et al258 found probable linkage of a form of congenital posterior polar cataract described by Maumenee in 1979338 to the haptoglobin locus. It is possible that these cataracts are allelic; however, further detailed morphologic studies, linkage studies, and mutational analysis will be needed to confirm this.

F. Volkmann type cataract (CCV) 

Volkmann-type congenital cataract (CCV), is an autosomal dominant trait named after the Danish family in which it was originally studied.238 The disorder is progressive with central and zonular cataract. Opacities are found in the embryonic, fetal, and juvenile nucleus and around the anterior and posterior Y-suture. Variable expression is seen ranging from barely visible opacities to dense cataracts.

The CCV locus is telomeric to the gene for glucose dehydrogenase, which maps to 1pter-p36.13.109 The enolase-1 gene (ENO1) is in the same region as CCV. ENO1 encodes tau-crystallin; however, ENO1 may not be a candidate gene as a family with hereditary red cell enolase partial deficiency did not have cataracts.227

A genetic variant of the Rh blood group system, known as the Evans phenotype or the D phenotype maps to chromosome 1p34-36.79., 244. The Evans phenotype has been linked with a cataract-causing locus by Huang and coworkers.172., 173. Rh polypeptides of human erythrocytes are polymorphic in nature. They may have a role in membrane structure and physiology.5., 16., 73.

G. Dominant zonular pulverulent cataract (CZP3) 

Dominant zonular pulverulent cataract is characterized by fine, dust-like opacities in various regions of the lens.246 In 1997, Mackay et al found linkage of this disorder to chromosome 13q in a five-generation English family.245 In 1996, Mignon et al had mapped the gene for gap-junction protein α-3 (GJA3, connexin46) to 13q11-q12.270 GJA3 had been found to be highly expressed in the lens.315 In 1999, Mackay et al uncovered mutations in GJA3 in two families with CZP3.246 Further evidence that mutations in the GJA3 gene cause CZP3 was provided by Rees et al.335

H. Autosomal dominant nonnuclear polymorphic congenital cataract 

In 1996, Rogaev et al studied a seven-generation family of 103 individuals affected with autosomal dominant nonnuclear polymorphic congenital cataract.344 Patients ranged in age from a few months to 70 years and all presented with congenital cataract. Opacities varied in shape, number, location, and color (crystal-like to snow-white). Linkage studies using a trinucleotide microsatellite marker in the crystallin gamma 1 gene (CRYG1) mapped this cataract locus to chromosome 2q33-q35.

I. Zonular cataract with sutural opacities 

Zonular cataract is the most common congenital cataract.314 Opacities are found in a discrete layer of fiber cells while the fibers internal and external to the opacity remain clear. Opacification may be dense, uniform, opaque or dotted/dustlike. The sutural opacities are at juxtaposed ends of secondary lens cells and often resemble the letter Y. These cataracts can be inherited in either a dominant or an X-linked pattern. In 1995, Padma et al studied a three-generation family with an unusual form of autosomal dominant zonular cataracts with sutural opacities.314 Linkage was found between the cataract and markers on chromosome 17q11-q12 near the crystallin beta A1 gene (CRYBA1). In 1999, Kannabiran and colleagues studied the same family and found a mutation in the CRYBA1 gene, resulting in the deletion of exons 3 and 4.197 A second family with cataracts and a mutation in CRYBA1 has been reported by Bateman and colleagues.29

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V. Glaucoma 

A. Primary open-angle glaucoma 

Primary open-angle glaucoma (POAG) is the most common form of glaucoma, accounting for approximately 3% of visual impairment in white and 7.9% of African Americans.330., 331. POAG has been divided into two groups: juvenile and adult, with overlapping clinical presentations. Juvenile onset POAG is a rarer form that typically affects individuals between age 3 and 20, and exhibits an autosomal-dominant pattern of inheritance.

Juvenile-onset POAG (GLC1A) was first mapped to 1q21-31.339., 366. Stone and colleagues identified mutations in a candidate gene that mapped to this region, in patients with the POAG.384 The protein encoded by this gene had been independently characterized as “trabecular meshwork-induced glucocorticoid response protein” (TIGR) in trabecular meshwork cells in culture.115., 303. The same protein, named myocilin, had also been localized to the outer segment cilium of photoreceptors by Kubota and colleagues.223

Wiggs et al studied 152 affected families with juvenile-onset and adult-onset POAG. They found mutations in the TIGR/myocilin gene were an uncommon cause of adult-onset (<5%) and juvenile-onset (8%) POAG.417 These results are consistent with the genetic heterogeneity seen in adult-onset POAG. The recent discovery of a gene, optineurin, involved in normal tension glaucoma and POAG, adds to the inventory.336

B. Congenital glaucoma 

Primary congenital or infantile glaucoma (GLC3) occurs in early childhood, usually within the first year of life, but may develop later up to 3 years of age. It is usually inherited as an autosomal recessive trait. Sarfarazi et al mapped a locus for primary congenital glaucoma, GLC3A, to 2p21.350 Mutations in the gene for cytochrome P4501B1 (CYP1B1) were identified in families that showed linkage to 2p21, and likely account for most cases of autosomal recessive congenital glaucoma.380 The CYP1B1 gene belongs to the P450 group of monoxygenases involved in the metabolism of a variety of substrates. A cytochrome P450-dependent arachidonic acid metabolite inhibits Na+, K+-ATPase in the cornea and may regulate corneal transparency and aqueous humor production.357

Mapping studies in eight families with congenital glaucoma has revealed a second locus, GLC3B, at 1p36.7 The gene for GLC3B has yet to be cloned.

C. Pigment dispersion syndrome 

In pigment dispersion syndrome, pigment granules from the iris pigmented epithelium are deposited on various ocular structures, including the trabecular meshwork. The disorder most frequently affects young myopic individuals. In 1981 Scheie and Cameron documented autosomal dominant inheritance in pigment dispersion syndrome.353 Two loci for pigment dispersion syndrome have been identified at 7q35-q3615 and at 18q11-q21.14 Although pigment dispersion syndrome is considered to be a secondary glaucoma, identification of the genes causing this condition may have a direct relationship with the pathogenesis of POAG.

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VI. Vitreo-retinal disorders 

A. Norrie disease and associated conditions 

Norrie disease (ND) is an X-linked recessive disorder characterized by congenital blindness due to bilateral congenital retinal dysplasia that progresses to phthisis bulbi. Progressive sensorineural deafness occurs in at least 25% of cases.405 The gene for ND (NDP) was mapped to Xp11.3 and encodes a protein called norrin whose function is yet to be elucidated.42., 78. Computer modeling of norrin suggests the presence of a so-called cysteine-knot motif, a tertiary structure commonly seen in members of the growth factor protein superfamily.268 Six conserved cysteine residues in the carboxy-terminus of the protein seem to be essential to assure proper folding by forming three disulfide bridges. Early reports of X-linked microphthalmia may have been Norrie disease; however a locus at Xq27-28 distinct from NDP does exist.151

Familial exudative vitreoretinopathy (FEVR) is a vitreoretinal dystrophy characterized by premature arrest of vascularization of the peripheral retina.363 It is inherited as an autosomal dominant or X-linked recessive trait with high pentrance and variable expressivity. Mutations in NDP have been identified in X-linked FEVR.77 Missense mutations in NDP may also play a role in the development of severe retinopathy of prematurity.364 The dominant form of FEVR maps to 11p13 and has been shown to be due to mutations in frizzled-4 (FZD4).343

B. Retinoschisis 

X-linked retinoschisis (RS) is the most common juvenile macular dystrophy seen in males. A cystic spokewheel maculopathy occurs in virtually all affected individuals as young as three months of age and may already be present at or before birth (Fig. 5). Approximately 50% of the patients have bilateral schisis cavities in the peripheral retina (Fig. 6). A reduced b wave amplitude is recorded with electroretinography. Affected males lose vision typically in the second decade of life. Vision thereafter remains stable through middle age with a further later decline to legal blindness.369 Complications may include vitreous hemorrhage and retinal detachment.

From clinical observations, the underlying cause of RS was thought to be a defect in the Müller cell, a glial cell of the retina which may play a role in the organization of the retinal architecture during development.77., 352. Histopathology of eyes affected by RS reveals splitting of the nerve fibre layer of the retina, degeneration of the photoreceptors, thinning of the ganglion cell layer and a focal absence of the retinal pigment epithelium. Sauer and coworkers identified a gene for RS at Xp22.2, designated RS1.352 The RS1 protein is expressed in rod and cone photoreceptors, and bipolar cells but not Müller cells.278 The predicted protein sequence contains a highly conserved discoidin domain implicated in cell–cell adhesion and phospholipid binding domain, a function consistent with the observed splitting of the retina in RS patients.352 Interestingly, mutation analysis has shown a significant rate of new mutations in RS.1

C. Wagner disease 

Wagner described a Swiss pedigree in 1938 with myopia, early cataract formation, liquefaction of the vitreous, retinal vascular changes and retinal pigmentary alterations.402 Clinicians disagreed in the past as to whether Wagner disease was separate from Stickler syndrome (hereditary arthro-ophthalmopathy). Stickler syndrome has extraocular manifestations: skeletal anomalies, micrognathia, deafness and eye findings: microphthalmia, anterior segment dysgenesis, high myopia, congenital glaucoma, cataract, and lens luxation. The distinctness of these conditions was established when Wagner disease was localized to 5q.66 Stickler syndrome was shown to be caused by mutations in the gene encoding the alpha-1 chain of type II collagen (COL2A1) found in vitreous and cartilage.131

Wagner disease is an autosomal dominant vitreoretinal degeneration without extraocular findings. Clinical expression varies from unaffected carriers to bilateral severe visual impairment. Erosive vitreoretinopathy (ERVR) is a condition very similar to Wagner disease. Retinal detachment occurs more frequently in ERVR. Brown and colleagues presented linkage evidence that ERVR and Wagner disease were allelic disorders; both mapping to 5q13-q14.66 IN 1999 Perveen et al refined the genetic and physical localization of Wagner disease locus to 5q14.3.322

D. Albinism 

Albinism may be classified as oculocutaneous albinism (OCA) affecting eyes, hair, and skin, and ocular albinism (OA) affecting only the eyes. OCA is an autosomal recessive disorder with at least ten variants and can be subclassified into two categories according to the presence or absence of tyrosinase activity in melanocytes: tyrosinase-negative OCA (OCA type I) and tyrosinase-positive OCA (OCA type II).225., 424.

1. Tyrosinase-related (OCA type I, OCA1) 

OCA type IA, is the most severe form of albinism, marked by profound hypopigmentation, photophobia, nystagmus, and a propensity to develop malignant skin tumors. It is caused by mutations in the tyrosinase gene. The variants of tyrosinase-negative OCA: the yellow mutant (type I-B) and temperature-sensitive mutant (type I-TS) have some residual enzyme activity and varying amounts of melanin are produced in hair, skin, and eyes.143., 209.

2. Tyrosinase-positive (OCA type II, OCA2) 

OCA type II is an autosomal recessive disorder characterized by no production of the brown-black pigment (eumelanin) in skin, hair, and eyes.376., 423., 425. Production of the yellow/orange pigment (pheomelanin) does occur in these tissues and accumulates with age so that infants may initially appear to be as severely affected as patients with OCA type I, but they acquire pigment during early to mid childhood. Visual deficits are generally less severe in OCA type II than in OCA type I patients. Ocular features of affected individuals with OCA type II are similar to those of OCA type I (iris transillumination, diminished or absent foveal reflex (Fig. 7), misrouting of the optic tracts, strabismus, nystagmus, and photophobia).86

By studying Bantu subjects in South Africa, Ramsay et al localized the OCA type II locus to 15q11.2-q12.334 The pink-eye dilution locus (p) on mouse chromosome 7 mapped to a region of synteny with human 15q. As such, they postulated that the OCA type II gene was homologous to the mouse pink-eye dilution gene, p. This hypothesis was confirmed in 1992 when Gardner and coworkers isolated the human homologue, P, of the murine p cDNA and found that it mapped to chromosome 15q11.2-q12.140 The P gene encodes an integral membrane transporter protein in melanosomes and exhibits structural homology to transporters of small organic molecules. Rinchik and coauthors hypothesized that the protein encoded may have a role in transporting tyrosine, the precursor to melanin biosynthesis.340

3. Brown oculocutaneous albinism (BOCA, OCA3) 

BOCA is characterized by a moderate reduction in pigmentation in African or African-American individuals.2., 54. A mutation in the mouse brown (b) gene, results in a mouse with a brown coat color instead of black.158., 179. The protein 5,6-dihydroxyindone-2-carboxylic acid (DHICA), encoded by the b gene, was termed the tyrosinase-related protein (TYRP-1) due to its similarity to tyrosinase. The human TRYP-1 gene mapped to chromosome 9p23.80., 84., 287., 294., 435. In 1996, Boissy and coworkers found a single base deletion in exon 6 of the TYRP-1 gene in African American fraternal twins (one normal and one with BOCA).55 The mutation deleted an A in codon 368, resulting in a premature stop codon at 384. Since the TYRP-1 transcript was not detected in OCA melanocytes using various TYRP-1 probes, it was hypothesized that there was a decrease in stability of the truncated protein.

Despite evidence that implicated the TYRP-1 gene, Manga and colleagues reported nine southern African patients with BOCA who had a deletion at the locus of the P gene.250 Although disease-causing mutations in the P gene could not be found in the other allele, a suggestion was made that BOCA may also be due to mutations in the P gene.

4. OCA4 

Another form of oculocutaneous albinism, OCA4, has been identified through candidate gene analysis. The mouse gene, underwhite (uw), when carried as a homozygous mutation causes severe hypopigmentation. In a screen of 102 patients with OCA who did not have mutations in TYR or the P gene, a single patient was found with a homozygous single base pair change in the human ortholog of uw that encodes a membrane associated transporter protein.302

5. Ocular albinism 

Ocular albinism (Nettleship-Falls) is an X-linked trait with findings predominantly restricted to the eye: iris transillumination, nystagmus, and foveal hypoplasia. The female carrier state of fundus-wide coarse RPE granularity led Falls117 to anticipate the Lyon hypothesis of random inactivation of one X chromosome in clonal cells of female carriers.240

Bassi and colleagues isolated a novel transcript from Xp22.3-p22.2 where ocular albinism had been mapped and subsequently identified mutations in this gene in patients.27 At first this protein was identified as simply a novel protein. Schiaffino and colleagues then reported its similarity to a group of G-protein-coupled receptors that function in intracellular transport.355

E. Color vision defects 

1. Pigment genes 

The visual pigment genes consist of the rod pigment gene, rhodopsin, and the three cone pigment genes.298 There is significant homology between the rhodopsin gene and the three cone pigment genes, suggesting that all four genes are derived from a common ancestral gene.301 In fact, the DNA sequences and the intron/exon organization of the red and green pigment genes are almost identical.

The genes encoding the red and green pigments have been examined by Southern blotting of genomic DNA from several color-normal males.298 The red pigment is always present in a single copy, but the green pigment is present as one, two, or three copies in a head-to-tail array on the X chromosome.298 The high degree of relatedness of these tandem genes and their close physical proximity often results in mispairing, unequal homologous recombination during meiosis, and changes in copy number.298., 299.

Human color vision is due to the absorption of light by three classes of cone photoreceptors with overlapping sensitivities at short wave lengths (blue), middle wave lengths (green) and long wave lengths (red) with maxima at 420, 530, and 560 nm, respectively.300 Inherited color-vision deficiencies are congenital and nonprogressive conditions. The common X-linked forms of color-vision anomalies are often referred to as red-green color deficiency, a reduced ability to match or discriminate colors in the mid-to long-wavelength spectrum and are due to mutations in the red and green cone pigment genes.301

The term tritanopia indicates weak or absent discrimination of short-wavelength blue-yellow stimuli. Inherited tritanopia is unique among color-vision deficiencies because of its autosomal dominant transmission. Analysis of the blue-cone pigment in a small group of families with tritanopia revealed a heterozygous missense mutation in the blue cone pigment gene on chromosome 7 which cosegregated with the disease.413., 414.

2. Blue cone monochromacy 

Blue cone monochromacy (BCM) is a rare X-linked recessive condition, sometimes mistaken clinically for rod monochromacy. BCM results from lack of both red and green cone sensitivities, and does not involve the blue cone pigment gene on chromosome 7.296 The physiologic functions of both rods and blue cones are preserved. Individuals with BCM have very poor or absent color discrimination, photophobia, reduced visual acuity (20/70–20/100), and pendular nystagmus. Visual acuity may improve slightly and nystagmus subside by adulthood.

Linkage of BCM to the red-green pigment locus (Xq28) was established by Lewis.230 Multiple classes of mutations can lead to BCM.297 Many patients carry only a single red or hybrid pigment gene with a missense mutation. Some patients have up to three pigment genes, each with a missense mutation. Others have various sized deletions of the proximal part of the red/green cone pigment gene cluster, the locus control region (LCR) that controls the expression of the red/green color genes. In all such cases, the deletion inactivates the adjacent red/green genes.

3. Rod monochromacy 

Total color deficiency is also referred to as complete achromatopsia or rod monochromacy. It is the severest form of color-vision deficiency, with a complete lack of color discrimination. Clinically, patients have marked reduction in visual acuity, and pronounced photophobia. Electroretinographic recordings confirm the complete lack of cone photoreceptor responses.

Four distinct loci have been mapped for rod monochromacy. The first locus was inferred in a 20-year-old white female with a 14;14 Robertsonian translocation.320 She was found to have maternal isodisomy. This finding suggested that a form of rod monochromacy mapped to chromosome 14 and supported the concept that uniparental isodisomy if found could provide a putative chromosomal assignment for a rare autosomal recessive disorder. Linkage analysis in a large inbred Iranian Jewish family showed a second locus for achromatopsia at 2q11.19 This region contained a candidate gene encoding the cone cyclic nucleotide-gated cation channel alpha 3 subunit (CNGA3). Mutation analysis of CNGA3 revealed missense mutations that cosegregated with color deficiency in the families analyzed.422 This gene is also mutated in forms of incomplete achromatopsia and cone dystrophy.421 A third gene has been implicated in achromatopsia, GNAT2, which encodes the cone photoreceptor-specific alpha-subunit of transducin, a G protein of the phototransduction cascade.217

Pingelapese blindness is better known as total color deficiency with myopia. The isolate was described initially by Brody and coworkers.65 The Pingelapese live on the eastern Caroline Islands in the Pacific. Clinically, they have severe photophobia, horizontal pendular nystagmus, amaurosis, and color deficiency, and gradually develop cataracts. Winck and colleagues performed a genome wide scan for linkage in Pingelapese kindred and identified a locus at 8q21-q23.418 Sundin and coworkers subsequently found that the genetic basis of Pingelapese achromatopsia is a recessive point mutation in the CNGB3 gene encoding the β subunit of the cone cyclic nucleotide gated channel.387

F. Retinitis pigmentosa 

Retinitis pigmentosa (RP) is a heterogenous group of retinal degenerations affecting approximately 1:3000 people and responsible for visual loss of 1.5 million people worldwide. Clinically, these disorders are characterized by night blindness, progressive loss of peripheral vision, and pigmentary changes in the retina, eventually leading to complete loss of vision (Fig. 8). The genetics of RP is complex with autosomal dominant, autosomal recessive, X-linked, and digenic patterns of inheritance. A retinal dystrophy that mimics RP may also be seen in association with mutations of the mitochondrial DNA. Over 50 responsible loci/genes have been mapped and/or characterized (RetNet database; www.sph.uth.tmc.edu/RetNet/disease.htm) by positional cloning, candidate gene approaches and deletion mapping. Many genes code for photoreceptor-specific proteins that play key roles in phototransduction and outer segment morphogenesis. Despite the large number of identified loci, a molecular defect cannot be found in more than 50% of patients with RP.

1. Autosomal dominant RP 

Autosomal dominant RP (adRP) accounts for 20% of all RP cases and is characterized by significant allelic and non-allelic heterogeneity. In 1990, Dryja and coworkers first reported that a P23H mutation in RHO was responsible for a form of adRP.106 Since that time more than 70 different RHO mutations have been linked to adRP and arRP. RHO mutations make up to 30% of all adRP.

Mutations in the RDS gene that encodes peripherin have been found mostly in families with adRP, although in some patients, mutations in this gene result in macular degeneration, pattern macular dystrophy, fundus flavimaculatus, cone-rod dystrophy, or bull's eye maculopathy.232 Different diagnoses have been assigned to relatives with the same mutation. Mutations in RDS account for about 5% of cases of adRP.

Mutations in the NRL gene cause adRP. NRL, located at 14q11.2, encodes a basic motif-leucine zipper DNA-binding protein that is highly and specifically expressed in adult retina. This gene has been shown to upregulate the activity of the rhodopsin promoter when it acts synergistically with the homeobox gene CRX.46

RP13, a form of adRP, located at 17p13.3, is due to mutations in the pre-mRNA processing factor gene, PRPF8.262 This gene encodes a highly conserved splicing factor that is expressed ubiquitously. This new gene offers compelling evidence for a novel pathway to retinal degeneration. PRPF31 is another pre-mRNA splicing gene. Mutations in this gene underlie adRP (RP11).398 RP11 is mapped to 19q13.4.8

Fascin is a protein specific to photoreceptors that acts to cross link actin into bundles.347 It is likely involved in the formation of the cilium connecting the inner and outer segments of rods and cones; and therefore may affect the formation of new discs. Mutations of the human retinal fascin gene (FSCN2) were predicted to underlie some forms of retinal degeneration and may cause 3.3% of adRP in Japan.401

The RP1 gene is the human homologue of the mouse rp1 gene that encodes a photoreceptor protein whose expression is modulated by oxygen levels. This gene mapped to the pericentric region of chromosome 8, previously identified as a locus for adRP in a large family from the the southeastern US.51 A mutation was found in this gene in the original family and three other families.327

2. Autosomal recessive RP 

To date, at least 14 genes and an additional six chromosomal loci have been identified for autosomal recessive RP (arRP). Not surprisingly, genes involved in the pathway of phototransduction are represented: rod cyclic nucleotide-gated channel alpha-subunit (CNGA1); the alpha and beta-subunits of rod cGMP-specific phosphodiesterase (PDE6A, PDE6B); and arrestin (SAG). In addition, genes involved in the pathway of vitamin A metabolism and its recycling in the eye underlie some forms of arRP: In cellular retinaldehyde-binding protein (RLBP1); retina-specific ATP-binding cassette transporter (ABCA4); and lecithin retinol acyltransferase (LRAT). Mutations in the RPE-retinal G- protein coupled receptor (RGR) were found in two cases of RP by Morimura and colleagues.282 RGR binds all-trans-retinol preferentially. Lecithin retinol acyltransferase (LRAT) acts to form 11-cis retinal from all-trans retinol in the retinal pigment epithelium. Mutations in this gene were found in three cases of retinal dystrophy, 2 of which clearly showed consanguinity.391

3. X-linked RP (Fig. 9) 

X-linked RP (xlRP) is genetically heterogeneous with at least 5 loci: RP2, RP3, RP6, RP23, and RP24. The first locus, RP2, was localized by linkage analysis to Xp11.3.48 The RP2 gene has been cloned and mutations in this gene may account for about 15–20% of xlRP families.160 A second locus, RP3, was mapped to Xp21.1 and accounts for 70% of affected xlRP families.290 The RP GTPase regulator gene (RPGR) was cloned from the Xp21.1 region by positional cloning.397 Another locus, RP15, was suggested at Xp22.13-22.11 in linkage analysis studies of a single family with X-linked dominant cone-rod dystrophy.261 Re-examination of a family member and analysis of the pedigree allowed the identification of a mutation in RPGR, allowing reclassification of the phenotype.265

4. Digenic RP 

Digenic inheritance, the interplay of mutations in two different genes resulting in a heritable eye disorder, is an important genetic concept. Families with digenic RP have mutations in both RDS and the ROM1 gene.26., 105. Affected individuals in these families are heterozygous for mutations in both genes. Their parents are heterzygous carriers of either a ROM1 or RDS mutation and are phenotypically normal. The pattern of inheritance mimics an autosomal recessive trait, when looking at the parental generation. Affected individuals may then transmit the disorder like a dominant trait, but the transmission ratio is 25% rather than 50%, as both mutations must be transmitted to the offspring in order for them to be affected.

5. Usher syndrome 

Usher syndrome (USH), is characterized by hearing impairment and RP, and is transmitted as an autosomal recessive trait. Three broad patterns have been recognized in families: Usher syndrome type I (USH1) characterized by congenital and severe-to profound hearing impairment with vestibular dysfunction; Usher syndrome type II (USH2), with early age moderate to severe hearing loss and normal vestibular function; and Usher syndrome type III (USH3), with adult onset progressive hearing loss. USH affects one child in 25,000 in the U.S.59 It is regarded as the most frequent cause of hereditary deaf-blindness. Six USH 1 loci, USH1A, 1B, 1C, 1D, 1E and 1F have been mapped to chromosomes 14q32, 11q13.5, 11p15.1, 10q21-q22, 21q21 and 10q21-22, respectively.

At present, five USH1 genes have been cloned: myosin VIIA, harmonin, a cadherin-like adhesion protein, protocadherin and usherin. USH1 is reported to be responsible for half of the Usher cases. The USH1B gene accounts for 75% of USH1 cases, and codes for myosin VIIA, a putative actin-based motor protein.410 The gene is expressed in the cochlear and vestibular hair cells as well as in the retinal photoreceptor and pigment epithelial cells from embryonic life onwards. Harmonin, the gene underlying USH1C, is a PDZ-containing protein expressed in the inner ear sensory hair cells.49., 396. The PDZ domain was named after three proteins that were first shown to contain this domain (PSD-95, DLG and Z0-1). Independently, Bolz and colleagues,56 and Bork and coworkers58 (2001) identified the gene for USH1D, CDH23. It is expressed in the retina and cochlea and encodes an intercellular adhesion protein. Mutations of protocadherin 15 have been found to cause USH1F.6

The gene for USH2A at 1q41 encodes a protein, usherin, that has laminin, epidermal growth factor and fibronectin motifs. These motifs are most commonly observed in proteins of the basal lamina, the extracellular matrix, and cell adhesion molecules. USH2C maps to 5q14-21.326 The gene for USH3 maps to 3q21-q25 and encodes a novel protein with transmembrane domains.186

6. Leber congenital amaurosis 

Leber congenital amaurosis (LCA) is a group of retinal degenerations that are recognized at birth or during the first few months of life. An infant presents with total blindness or greatly impaired vision, nystagmus, an extinguished electroretinogram (ERG) and a range of fundus findings (Fig. 10). Many of the children develop a characteristic eye poking behavior (digito-ocular sign of Franceschetti). Hypermetropia and keratoconus frequently develop in the course of the disease. It is inherited as an autosomal recessive, rarely as an autosomal dominant trait. While six genes have been identified as mutated in cases of LCA, the genetics of the majority of cases remains unresolved.

The first gene for LCA was mapped to chromosome 17p13.1 (LCA1).321 Using a candidate gene approach, mutations were identified in the photoreceptor-specific guanylate cyclase gene (GUCY2D). Mutations in GUCY2D result in impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels. Consequently, the cGMP concentration in photoreceptor cells cannot be restored to the dark level, leading to a state equivalent to constant light exposure.

Mutations in RPE65 cause LCA.252 The gene encodes a 65-kD protein specific to the retinal pigment epithelium (RPE). RPE65 is believed to act as the isomerase catalyzing the conversion of all-trans-retinyl-ester to 11-cis-retinol in the RPE, an essential step in the metabolism of vitamin A. RPE65 maps to 1q31. RPE65 gene therapy in the Briard dog restored visual function, and efforts are now underway to develop a human gene therapy.3

Mutations in CRX, a novel photoreceptor-specific homeobox gene (19q13.3) have been found in autosomal dominant RP and recessive LCA.133 LCA3, has been mapped to 14q24, but the gene remains to be identified. LCA4 was mapped to 17p13.1 by linkage analysis. The gene was cloned and encodes the protein, arylhydrocarbon-interacting receptor protein-like 1 (AIPL1). The gene is expressed in photoreceptors and pineal gland. LCA5 has been mapped to 6q11-16 by linkage analysis.97 Lotery and coworkers described novel mutations in the crumbs homolog 1 gene (CRB1) that cause LCA.235 Finally, a novel gene called RPGIP1 for RPGR-interacting protein is located at 14q11.102 Recessive mutations in this gene cause a degeneration of both rod and cone photoreceptors early in life with typical signs of LCA.102

7. Retinitis punctata albescens (RPA) 

Retinitis punctata albescens is a form of night blindness in which the fundus shows discrete uniform white dots or flecks with greatest density in the midperiphery and no macular involvement. Both autosomal dominant and autosomal recessive modes of inheritance have been suggested. An autosomal dominant form has been linked to a mutation in the RDS gene.195 A phenotype similar to RPA is also seen in Bietti crystalline corneoretinopathy (BCD) which is inherited as an autosomal recessive. BCD has been mapped to 4q35-tel.185 Autosomal recessive RPA is due to mutations in RLBP1, the gene encoding cellular retinaldehyde-binding protein.69

8. Congenital stationary night blindness (CSNB) 

CSNB comprises a group of disorders characterized by congenital onset of nonprogressive nyctalopia, subnormal visual acuity, and absence of pigmentary degeneration of the retina. Strabismus and nystagmus are often associated with this group of disorders.37 Three monogenic modes of inheritance have been described: autosomal dominant, autosomal recessive, and X-linked recessive.

Electroretinography (ERG) has a key diagnostic role in CSNB. CSNB has been divided into the Riggs type and the Schubert-Bornschein type or negative-type ERG. The Riggs type ERG (with no a wave) is seen in the autosomal dominant form of CSNB. In this form of CSNB, Dryja and colleagues reported a mutation in the gene encoding the alpha subunit of rod tranducin (GNAT1), the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade.104 GNAT1 is located at 3p21. The absence of the rod a wave in this form of stationary night blindness is used as evidence of physiologic effects on the rod photoreceptor. The Schubert-Bornschein type ERG has a normal a wave, but reduced or absent b wave. The Schubert-Bornschein ERG suggests normal rod function but a deficit at the level of bipolar cell layer or the synaptic connection between rod photoreceptors and the bipolar cells.291

Clinical heterogeneity among families with CSNB led to the suggestion that the X-linked form of CSNB be classified as either complete (CSNB1) or incomplete (CSNB2).35 The classification was based on abnormalities both of the ERG and dark-adaptation thresholds. In the complete form of CSNB, both the scotopic b wave recorded in response to dim blue flashes and the early oscillatory-potential wavelets are nonrecordable. The night blindness is profound, as documented by the lack of rod adaptation to darkness.291 In the incomplete form of CSNB, the scotopic b wave is recordable, although it is subnormal in amplitude. The dark-adaptation thresholds are only slightly elevated above normal.291 Genetic analyses of families with X-linked CSNB supported two loci, one for complete (CSNB1) mapped to Xp11.4-p11.3 and a second locus for incomplete type of CSNB (CSNB2) mapped to Xp11.23.61

CSNB2 encodes an L-type voltage-gated calcium channel, alpha-1 subunit (CACNA1F) and mutations in this gene result in loss of function.37 The gene for complete CSNB (CSNB1) encodes a glycosylphosphatidylinositol (GPI)-anchored protein, called nyctalopin.36 This protein has cystine clusters and 11 leucine-rich repeats, and is a new member of the small leucine-rich proteoglycan (SLRP) family. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-biploar cells, leading to poor vision in patients with CSNB.36

9. Oguchi disease 

Oguchi disease is a rare autosomal recessive form of stationary night blindness due to mutations in either arrestin (S-antigen)135 or rhodopsin kinase.83 These two proteins are members of the rod phototransduction pathway. Rhodopsin kinase acts with arrestin in shutting off rhodopsin after it has been activated by a photon of light and defects in these genes impair rod sensitivity in dim light. Patients with this disease show a distinctive golden-brown fundus coloration that develops as the retina adapts to light, called the Mizuo phenomenon.

10. Choroideremia 

Choroideremia (CHM) is a sex-linked chorioretinopathy in which both carrier females and affected males show signs of patchy chorioretinal atrophy. Signs begin earlier in the males in the first decade of life and are progressive, leading to loss of peripheral vision. The central macula is preserved until late in the disorder, but eventually sight is lost. The carrier female usually shows mild signs with no loss of peripheral vision and a slow progression of signs. In general, choroideremia is not clinically confused with RP; however, the end stages of each disease process may be remarkably similar.242

The CHM gene encodes Rab escort protein-1, previously termed component A of geranylgeranyl transferase.358 REP-1 is necessary for the efficient prenylation of specific Rab proteins in the eye. Rab proteins are small GTPases that function in targeting of vesicle transport within cells. Another autosomal gene has been cloned that encodes a protein REP-2.87 REP-2 is likely not sufficient to allow prenylation of specific Rab proteins within the eye, accounting for the progressive chorioretinal degeneration in both the hemizygous male with mutations in the CHM gene and the carrier female. All mutations to date result in a truncation of the normal gene product and its absence.

In counseling patients with the presumptive diagnosis of CHM, a sex-linked pattern of inheritance should be sought. Identification of carrier females can be undertaken with clinical examination. Confirmation of the clinical diagnosis may be provided by direct sequencing of the gene or immunoblot analysis to demonstrate absence of REP-1 in affected males.243

G. Macular dystrophy 

1. Sorsby fundus dystrophy 

Sorsby fundus dystrophy (SFD) is an autosomal dominant macular degeneration developing in the third or fourth decade.375 Central vision is lost as a result of subretinal neovascularization and subsequent atrophy of the choriocapillaris, retinal pigment epithelium (RPE), and retina. A macular disciform scar and extension of chorioretinal atrophy to the fundus periphery may occur in later stages. SFD and AMD share some clinical features. Similar to early AMD, in early SFD a confluent, lipid-containing deposit accumulates within Bruch's membrane.63., 72. Bruch's membrane is multilayered, composed of collagen, laminin, fibronectin, proteoglycans, and glycosaminoglycans.231 During normal development, production and turnover of extracellular matrix molecules involves a family of tightly regulated matrix metalloproteinases (MMPs) and other proteolytic enzyme groups such as serine or cysteine proteinases.98., 256. Remodeling of the extracellular matrix is an important process and MMP activity is controlled at the level of transcription and enzyme activation/inhibition.256

Apte et al isolated overlapping cDNAs encoding TIMP3, a novel member of the family of tissue inhibitors of metalloproteinases and mapped it to chromosome 22q12.1-q13.2.18 TIMPs are a group of zinc-binding endopeptidases involved in the degradation of the extracellullar matrix. In 1994, Weber and colleagues linked SFD to markers on 22q13-qter and using the candidate gene approach, found point mutations in TIMP3 in SFD patients from two pedigrees.408 The mutations predicted a change in the tertiary structure of TIMP3, resulting in improper function of the mature protein. Altered TIMP3 function would lead to abnormal subretinal deposits, disturbing the balance between buildup and breakdown of the extracellular matrix.408 This deposit may act as a barrier to diffusion of nutrients to the photoreceptors and account for impaired dark-adaptation in some SFD subjects.72., 378. Despite the similarity in phenotypes between SFD and AMD, no mutations have been found in the TIMP-3 gene in a screen of AMD patients.120

2. Stargardt macular dystrophy 

Stargardt macular dystrophy (STGD) is an autosomal recessive disorder first described in 1909.377 Onset occurs between 7 and 12 years of age, followed over a period of several months by bilateral loss of central vision. Depigmentation and atrophy of the macular retinal pigmentary epithelium (RPE) is usually accompanied by perimacular yellowish spots (Fig. 11).125., 129., 155., 377. Peripheral visual fields remain normal throughout life as degeneration is limited to the macula. STGD is a frequent cause of macular degeneration in children with an incidence of 1 in 10,000,50 and accounts for 7% of all retinal dystrophies.198

Fundus flavimaculatus (FFM) is characterized by uniformly distributed yellow spots in the fundus.141 The age of onset of FFM occurs later than STGD, ranging from 17 to 60 years in adult patients, and its progression is slower. Symptoms include loss of color vision, photophobia, paracentral scotoma and slow dark adaptation. Central vision loss occurs late in FFM. FFM and STGT are now believed to be allelic disorders, despite differences in age of onset, clinical course and severity.141 Linkage studies by Kaplan et al,10., 200. and Gerber et al141 mapped STGD and FFM, to 1p21-13 and 1p13, respectively. In 1997, a gene (ABCA4) encoding an ATP-binding cassette (ABC) transporter was mapped to 1p22 by Allikmets et al and mutations were found in this gene in STGD families.10 The ABCA4 gene is expressed in rod and cone photoreceptors.279 As an example of the value of understanding phenotype/genotype correlations, Rozet et al found that nonsense mutations truncating the ABCA4 gene resulted in STGD, whereas missense mutations resulted in FFM.345

An autosomal dominant form, Stargardt-like macular dystrophy, is seen uncommonly. Patients have a macular dystrophy with peripheral flecks that do not extend much beyond the central macula. Recently a gene, ELOVL4, thought to function in the pathway of very long chain fatty acid synthesis has been found that is mutated in affected individuals.434

3. Best vitelliform macular dystrophy 

Best vitelliform macular dystrophy (BMD, VMD2) is a slowly progressive macular degeneration with onset in the teens.148 Typical egg yolk-like macular lesions (Fig. 12), and abnormal electrooculographic (EOG) findings characterize BMD.91 It is inherited in an autosomal dominant fashion.148 Although many patients remain free of fundus abnormalities throughout life, BMD is considered fully penetrant because nearly all carriers of the defective gene have an abnormally low Arden ratio (the light peak to dark trough of the electro-oculogram).20

In the vitelliform stage, lipofuscin accumulates within and beneath the RPE, but generally does not impair visual acuity.409 The egg-yolk lesion in the macula can remain stable for many years without affecting vision. Subsequently, in a process called “scrambling the egg,”62 the macular egg-yolk becomes deeply and irregularly pigmented, and visual acuity is affected. Loss of central vision may eventually occur as a result of RPE atrophy and/or choroidal neovascularization.409 In 1992, Stone et al linked BMD to chromosome 11q13.386 Petrukhin et al subsequently identified disease-specific mutations in a novel retina-specific gene, bestrophin.324

H. Retinoblastoma 

Retinoblastoma (RB) is an embryonic neoplasm of retinal origin. Although it is the most common intraocular malignant tumor of childhood, it is relatively rare (1:20,000 live births)(Fig. 13). About 5% of RB patients have either a deletion or translocation at 13q14. The RB1 gene was then cloned from this region. RB occurs in both hereditary and nonhereditary forms. Whereas 90% penetrance is seen in most families, families with low penetrance have been reported.234 Molecular genetic techniques of gene amplification and DNA sequence analysis have shown that RB arises from two mutational events.216 Mutation in one allele of the BR1 gene leads to a predisposition for RB. Tumor development is initiated by inactivation of the second RB1 allele. If both mutations occur in the same somatic or postzygotic retinal cell, a single, unilateral, noninheritable retinoblastoma occurs. In the hereditary form, the first mutation occurs in a germinal cell (gonadal) and the second mutation in a somatic cell (retina), resulting in multiple retinal tumors in one or both eyes. Because every cell in the body has the germ line mutation, the patient is at risk for malignancies at other sites.

RB1 is a large tumor-suppressor gene of 27 exons. The protein (pRB) inhibits cell proliferation through interaction with the transcription factor, E2F.107 Germ line mutations of RB1 lead to a 40,000 fold relative risk for RB, a 500-fold risk for sarcoma (increased to 2000 by therapeutic radiation). In the absence of pRB, cells proliferate, further mutations occur and a retinal tumor emerges.134., 139.

Approximately 50% of all cases of RB are heritable. All patients with familial, bilateral, or unilateral multifocal RB are regarded as carriers of an RB1 germ-line mutation. In addition, survivors of isolated unilateral RB may have children affected by RB. Klutz et al, by using precise molecular studies of RB1 in the tumor and blood of children with unilateral RB, showed that 9% of patients with unilateral RB have a RB1 germ-line mutation.214 Molecular studies can be important in patients with unilateral RB. These patients might be the first evidence in a family of low-penetrance of an RB1 mutation.234 A tumor may then grow unobserved if relatives have not been screened. Unfortunately, practical molecular testing of patients with unilateral RB usually requires that tumor is available to permit identification of RB1 mutations. Mutation screening of peripheral blood DNA can however detect oncogenic mutations for most patients with bilateral or familial RB. Although molecular testing for RB1 mutations is still not freely available, a comparison of the costs of molecular genetic testing versus infant screening approaches has indicated that mutation analysis will help reduce health-care expenses. Whether a case of RB is sporadic or familial, first degree relatives are screened regularly with ophthalmic examinations. Molecular genetic analysis can remove this burden if an individual is found to not carry a mutation in the RB1 gene.138., 308.

I. Gyrate atrophy 

Gyrate atrophy is an autosomal recessive degeneration of the choroid and retina.389 Clinical manifestations usually start in the first decade with night blindness and progressive myopia. Small, sharply demarcated, circular areas of chorioretinal atrophy are observed at the age of 5 years.193 Enlargement of atrophic areas is observed in the second and third decades, with peripapillary lesions. The optic disc stays pink and healthy. Hyperpigmentation and occasional crystals can be seen at the margins of the atrophic areas.192 By the second or third decade of life, posterior subcapsular cataracts become visible and surgery is necessary.191 During the later phases of the disease, but before the atrophy becomes complete, the electroretinogram (ERG) is decreased.

Ornithine-delta-aminotransferase (OAT) is a nuclear-encoded mitochondrial matrix enzyme which catalyzes the reversible interconversion of ornithine and alpha-ketoglutarate to glutamate semialdehyde and glutamate. The OAT gene maps to chromosome 10q26,24., 276., 309., 310., 332. and mutations in this gene cause gyrate atrophy.394., 395. Plasma, urine, spinal fluid, and aqueous humor ornithine levels are 10 to 20 times higher than normal.370 The mechanism by which OAT deficiency and hyperornithinemia lead to chorioretinal degeneration is not known.

J. Cone and cone rod dystrophies 

1. Cone dystrophy 

Although grouped with the cone-rod dystrophies, X-linked cone dystrophy (COD1) affects primarily the cone photoreceptors, as witnessed by the ERG. Affected males have photophobia, myopia, abnormal color vision, and poor central vision with central scotomas. The ophthalmologic findings show progression from retinal pigment epithelial changes, to bull's eye maculopathy and finally central macular atrophy.180 Linkage analysis including a large pedigree clearly established COD1 as a separate genetic disorder mapped to Xp11.4 between RP2 and RP3.362 Some COD-1 families however have mutations in RPGR that normally cause X-linked RP (RP3).94

Another form of cone dystrophy (COD3) displays an autosomal dominant pattern of inheritance. In a large British kindred, linkage analysis first mapped the disorder to 6p21.1 and subsequent molecular genetic analysis of the guanylate cyclase activator-1A (GUCA1A) found a mutation in all affected family members.317 Intrafamilial variability can be seen with mutation of the GUCA1A gene with both cone and cone rod dystrophy phenotypes.101., 232.

2. Cone rod dystrophies 

The cone rod dystrophies are inherited in an autosomal dominant or autosomal recessive pattern and can exhibit various phenotypes including: macular dystrophy, pattern dystrophy, and severe retinal dystrophy.232 This spectrum includes minimally affected individuals with a late onset disorder to others with end stage RP within the same pedigree. Electrophysiology, visual field examination, and color vision testing and family history are important to define the phenotype. The ERG shows a predominant effect on the cone ERG with a relatively preserved rod ERG in its early phases. Although many loci have been suggested, we discuss only 3 for which the genes have been cloned.

CRX, the cone rod homeobox transcription factor, has been shown to be mutated in cone rod dystrophy (CORD2).132 Curiously, this same gene is mutated in Leber's congenital amaurosis (LCA4). The CRX gene is expressed in photoreceptors but it may have a wider role in the maintenance of neurotransmission in the retina.232

Using linkage analysis, Kelsell and coworkers (1997) mapped a locus (CORD6) at 17p13.1,202 and subsequent molecular studies revealed mutations in the retinal guanylate cyclase (GUCY2D) gene.204 This is the same gene that is mutated in a form of Leber's congenital amaurosis (LCA1) and may explain the early onset of CORD6 in childhood.152

Some forms of cone rod dystrophy exhibit an autosomal recessive mode of inheritance. ABCA4, the gene that is mutated in Stargardt macular dystrophy, is commonly found mutated in autosomal recessive cone rod dystrophy.257

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VII. Optic nerve 

A. Dominant optic atrophy, Kjer type (OPA1) 

Kjer-type juvenile optic atrophy (OPA1) is an autosomal dominant disorder with a frequency of 1 in 50,000.212 OPA1 is characterized by insidious onset before 8 years of age, reduced central vision, loss of color perception predominantly in the blue-yellow axis, temporal or diffuse disk pallor (Fig. 14), and a slowly progressive course.400

Linkage analysis of three Danish families linked the OPA1 gene to 3q28-q29.108 Other studies have confirmed this linkage and narrowed the interval, with no evidence of genetic heterogeneity in Cuban,239 French,57 British,188 and American families.67 OPA1 is due to mutations in a gene that encodes a mitochondrial dynamin-related protein, thought to function in the maintenance of mitochondrial morphology.9., 93. Mutations in the OPA1 gene are highly penetrant but show variable expression. Individuals in a family may have visual impairment ranging from mild to severe.

A second locus for dominant optic atrophy was linked to 18q13.2-q12.3.206 This form of optic atrophy showed interfamilial variation similar to families linked to 3q.

B. Oculorenal syndrome and Pax2 mutations 

Pax2 is expressed in both the uretheric bud and surrounding mesenchyme of mouse embryos. In the eye, Pax2 is expressed in the ventral optic stalk, the portion of the optic vesicle that will generate the optic nerve, and in the optic nerve head. It is also expressed in the developing inner ear of the mouse embryo.349 In humans, mutations in PAX2 have been identified in patients with the autosomal dominant oculorenal syndrome of optic nerve colobomas and renal malformations.12 Auditory and central nervous system abnormalities may occur. PAX2 mutations can show extreme intrafamilial and interfamilial variability. The gene for PAX2 maps to 10q25.118

C. Leber hereditary optic atrophy (LHON) 

LHON is a maternally inherited optic neuropathy that is associated with mutations in the mitochondrial DNA (mtDNA).403 The mtDNA encodes for a number of protein components of the mitochondrial respiratory chain and oxidative phosphorylation system, as well as some 20 transfer RNAs and two ribosomal RNAs. A plethora of mtDNA mutations have been identified in families with LHON resulting in confusion as to the pathogenic significance of each mutation. Five primary mutations at basepairs 3460, 4160, 11778, 14484, and 15257 represent the majority of mutations in affected families.175 LHON manifests typically as a painless loss of central vision within the second and third decade of life. The age of onset may vary widely from 1 to 70 years.171

The eyes can be affected simultaneously or sequentially, with an average time interval of about 2 months. Neuro-ophthalmic examination commonly reveals peripapillary telangiectasia, pseudopapilledema and vascular tortuosity.304., 305. The probability of visual recovery varies with the type of mutation: 4% of 11,778 patients recover 36 months after onset; 22% of 3,460 patients recover after 68 months; 28% of 15,257 patients recover after 16 months; and 37% of 14,484 patients recover after 16 months.312., 341., 342.

Although LHON is considered to be familial, many individuals represent isolated cases. Interestingly, in Asia, greater than 90% of LHON patients harbor the 11778 mutation. Based on reported cases, 50–80% of males and 8–32% of females who carry a mtDNA mutation will be at risk of significant visual loss.255

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VIII. Eye development disorders 

A. Microphthalmia 

Microphthalmia may be designated as simple (without other ocular disease), complex (associated with cataract, retinal or vitreous disease), or more complex (with malformations).411., 412. Up to 80% of cases occur as part of syndromes that include systemic malformations, especially cardiac defects, facial clefts, microcephaly, and hydrocephaly.196 Microphthalmia can be further divided into colobomatous and non-colobomatous categories on the basis of associated uveal abnormalities.28., 404. Microphthalmia can be an isolated or familial disorder: autosomal dominant,346 autosomal recessive,219 and X-linked recessive.151 A locus for autosomal dominant colobomatous microphthalmia has been found at 15q12-q15 in the study of a Sephardic Jewish kindred.283

Many chromosomal anomalies have been associated with uveal coloboma, micropthalmia, anophthalmia, or a combination of these defects, including: trisomy 13 (Patau), 4p- (Wolf-Hirschorn), 11q-, 13q-, 18q-, ring 18, trisomy 18 (Edward), cat-eye syndrome (marker 22) and Klinefelter syndrome (XXY).404 The yield of chromosomal studies is poor in isolated microphthalmia/coloboma but increases significantly if there is mental retardation or other congenital malformation. Prenatal high-quality ultrasonography may detect microphthalmia.

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IX. Conclusion 

Ophthalmology has contributed broadly to the clinical delineation of genetic disorders. In the last 20 years, molecular genetics has uncovered the complexity of ocular genetics. Eye genes are now being mapped and cloned at an incredible rate. The information presented in this paper may provide a clearer summary of the genetics of heritable ocular disorders and serve as a starting point in the investigation of families. More indepth research may be required to provide an up-to-date understanding of particular conditions before counseling patients and families.

The investigation of a single case of a suspected heritable ocular disorder begins with a careful family history. The examination of other family members will sometimes provide important clues as to the clinical diagnosis. Supplemental molecular genetic diagnosis in some cases can then provide a specific diagnosis for the index case and the entire family.

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Method of literature search 

The sources of information for this review were accumulated over a 3-year period (1999–2002) by hand-searching articles from major ophthalmicand genetic journals. Where possible the current nomenclature and references were verified with citations in OMIM, RetNet, and Genew.

Databases used:

a.Genew, HUGO Gene Nomenclature Committee (HGNC), Department of Biology, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK. World Wide Web URL: www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl. Wain HM, Lush M, Ducluzeau F, Povey S. Genew: The Human Gene Nomenclature Database. Nucleic Acids Research 2002 Vol. 30, No. 1 169-171. Accessed October 2002.

b.OnLine Mendelian Inheritance in Man, OMIM™. Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). World Wide Web URL: www.ncbi.nlm.gov/Omin/.

c.Retinal Information Network, RetNet™. The Hermann Eye Center, The Human Genetics Center. The University of Texas Houston Health Science Center. World Wide Web URL: www.sph.uth.tmc.edu/retnet/.

d.GeneTests. GeneClinics: Medical Genetics Information Resource (database online). © 1993–2002 University of Washington and Children's Health System. Updated weekly. Available at www.geneclinics.org or www.genetests.org. Accessed October 2002.

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Outline 

I.Introduction

II.Anterior segment conditions
A.Aniridia

B.Axenfeld-Rieger malformation

C.Peters anomaly


III.Corneal dystrophies
A.βig-h3

B.Meesmann dystrophy


IV.Lens disorders
A.Aculeiform cataract

B.Polar catatact
1.Anterior polar cataract 1

2.Anterior polar cataract 2

3.Posterior polar cataract


C.Cerulean cataract
1.Cerulean cataract type I

2.Cerulean cataract, type II


D.Coppock and Coppock-like cataract
1.Lamellar zonular pulverulent cataract (Coppock)

2.Coppock-like cataract


E.Marner-type cataract

F.Volkmann-type cataract

G.Dominant zonular pulverulent cataract

H.Autosomal dominant nonnuclear polymorphic congenital cataract

I.Zonular cataract with sutural opacities


V.Glaucoma
A.Primary open-angle glaucoma

B.Congenital glaucoma

C.Pigment dispersion syndrome


VI.Vitreo-retinal disorders
A.Norrie disease and associated conditions

B.Retinoschisis

C.Wagner disease

D.Albinism
1.Tyrosinase related (OCA1)

2.Tyrosinase positive (OCA2)

3.Brown oculocutaneous (OCA3)

4.Oculocutaneous albinism type 4 (OCA4)

5.Ocular albinism


E.Color vision defects
1.Pigment genes

2.Blue cone monochromacy

3.Rod monochromacy


F.Retinitis pigmentosa
1.Autosomal dominant RP

2.Autosomal recessive RP

3.X-linked RP

4.Digenic RP

5.Usher syndrome

6.Leber congenital amaurosis

7.Retinitis punctata albescens

8.Congenital stationary night blindness

9.Oguchi disease

10.Choroideremia


G.Macular Dystrophy
1.Sorsby fundus dystrophy

2.Stargardt macular dystrophy

3.Best vitelliform macular dystrophy


H.Retinoblastoma

I.Gyrate atrophy

J.Cone and cone rod dystrophies
1.Cone dystrophy

2.Cone rod dystrophy



VII.Optic nerve
A.Dominant pptic atrophy, Kjer type (OPA1)

B.Oculorenal syndrome and PAX2 mutations

C.Leber hereditary optic neuropathy


VIII.Eye development disorders
A.Microphthalmia


IX.Conclusion

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References 

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Glossary

Glossary of Terms

 -(In compiling the glossary of terms, the authors referred to www.genomicglossaries.com.)

Allele

 -one or more alternate forms of a gene.

Antisense

 -the specific sequence of nucleotides that binds to the sense or coding sequence.

Candidate gene approach

 -the search for mutations in a known gene in the map location of a genetic trait.

cDNA

 -complementary DNA, usually ascribed to the coding sequence of a gene that makes a protein.

Chaperone

 -a protein assisting in transport.

Contiguous gene syndrome

 -a deletion of a chromosome that results in the loss of a number of genes individually cause specific phenotypes.

Deletion mapping

 -assignment of a gene to a map location in the genome after identifying a deletion of the chromosome at that location.

Digenic inheritance

 -a pattern of inheritance in a family with mutations in two separate, perhaps unlinked genes.

Domain

 -in a protein that results in a particular function.

Dominant negative

 -deleterious allele which produces a more severe phenotype than a null allele at the same locus (i.e., interferes with function of the other normal allele.

Exon

 -a sequence of nucleotides that represents part of the final mRNA that is translated into the functional protein.

Frameshift

 -a mutation that shifts the sequence of codons and results in an altered amino acid sequence.

Genome

 -the sum total of heritable elements of a cell.

Genomic DNA

 -the total DNA including coding and non-coding sequences.

Haploinsufficiency

 -the loss of one allele at a genetic locus.

Heterozygous

 -having two allelic variants of a gene.

Homeobox

 -a conserved sequence of DNA with homology to the homeotic genes in D. melanogaster involved in development.

Homeodomain

 -a DNA-binding domain within a homeotic gene (see also homeobox).

Homologous

 -having similar DNA sequence.

Homologous recombination

 -exchange of chromosomal material within regions of similar sequence.

Homologue

 -chromosomes with identical genetic loci.

Intron

 -a sequence of DNA between exons, sometimes referred to as an intervening sequence.

Karyotype

 -the specific chromosomal complement of an individual.

Linkage

 -the association of genetic traits due to their localization within the same chromosome.

Locus

 -a specific site within a chromosome.

LOD score

 -logarithm of the odds of linkage.

Maternal (paternal)isodisomy

 -a type of uniparental disomy in which both copies of a maternal (or paternal chromosome are the same).

Missense mutation

 -a single nucleotide change that results in a changed single amino acid in a protein.

Meiosis

 -the process by which chromosomes are reduced in number and distributed into sexual reproduction.

Mosaicism

 -two or more cell lines that differ in their genetic make-up (sometimes chromosome number).

Non-allelic heterogeneity

 -variation not simply based on alleles of a single gene, but possibly multiple genes that cause a similar phenotype.

Orthologue

 -a sequence of a gene that has diverged during speciation having possibly the same function.

Penetrance

 -whether or not a trait is observed in a patient (e.g., cataract absent or present).

Phenotype

 -the observed characteristics of a gene or allele in an individual.

Point mutation

 -the substitution of a single base pair.

Positional cloning

 -linking known sequences of DNA to map the location of a disease gene.

Promoter

 -a region of DNA involved in the initiation of transcription of a gene.

Restriction fragment length polymorphism

 -the sequence variation between chromosomes that results in heritable size fragments of DNA.

Restriction site

 -the specific palindromic sequence of DNA that is recognized and cleaved by a restriction endonuclease.

Robertsonian translocation

 -the fusion of two acrocentric chromosomes to result in a metacentric chromosome with the loss of chromosomal material from the p-arms (short arms) of the acrocentric chromosomes.

Southern blot

 -the transfer of genomic DNA to a nylon membrane and probing with radiolabeled DNA.

Trinucelotide microsatellite marker

 -heritable repeated trinucleotide elements in the DNA that are used in mapping studies.

☆ The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this manuscript. The authors are very grateful for many helpful comments from Elise Héon, Muriel Kayser-Kupfer, Paul Sieving, and Michael Walter who read all or part of the manuscript.

PII: S0039-6257(03)00177-2

doi:10.1016/j.survophthal.2003.12.003

Survey of Ophthalmology
Volume 49, Issue 2 , Pages 159-196, March 2004

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