Genetic Origins of Cataract

SPECIAL ARTICLE Genetic Origins of Cataract

Alan Shiels, PhD; J. Fielding Hejtmancik, MD, PhD

ataract, which can be defined as any opacity of the crystalline lens, results when the refractive index of the lens varies significantly over distances approximating the wave- length of the transmitted light.1 This variation in the refractive index can result from changes in lens cell structure, changes in lens protein constituents, or both.2 Cata- Cracts are generally associated with breakdown of the lens microarchitecture. Vacuole formation can cause large fluctuations in optical density, resulting in light scattering. Light scattering and opacity also can occur if there are significant concentrations of high-molecular-weight protein aggregates, roughly 0.1 nm or more in size. The short-range, ordered packing of the crystallins, which make up more than 90% of soluble lens proteins, is important for the maintenance of lens crystallins in a homogeneous phase.

Defined by age at onset, a congenital or in- It seems likely that when mutations in fantile cataract is visible within the first crystallins or other lens proteins are suffi- year of life; a juvenile cataract occurs cient in and of themselves to cause pro- within the first decade of life; a presenile tein aggregation they usually result in con- cataract occurs before age 45 years; and genital cataract, while if they merely senile or age-related cataract, thereafter. increase susceptibility to environmental in- The boundaries between different types of sults, such as light, hyperglycemic, or oxi- cataract are approximate; for example, dative damage, they might contribute to some investigators would consider juve- age-related cataract.3 Thus, hereditary con- nile cataracts to occur before 20 years of genital cataracts tend to be inherited in a age and age-related cataracts to occur af- mendelian fashion with high penetrance, ter 60 years of age. In addition, subtle cata- while age-related cataracts tend to be mul- racts might not be seen for years after they tifactorial, with both multiple genes and en- occur, especially if they are asymptom- vironmental factors influencing the phe- atic. The age at onset of a cataract does not notype. This makes them significantly less necessarily indicate its etiology. Congen- amenable to genetic and biochemical study. ital cataracts may be hereditary or second- ary to a noxious intrauterine event (eg, ru- CONGENITAL CATARACT bella). Cataracts associated with a systemic or genetic disease may not occur until the Hereditary cataracts are estimated to ac- second or third decade (eg, cataracts as- count for between 8.3% and 25% of con- sociated with retinitis pigmentosa). Even genital cataracts.4,5 The lens alone may be age-related cataracts, generally thought to involved, or lens opacities may be associ- be due to multiple insults accumulated ated with other ocular anomalies, such as over many years, have a genetic compo- microphthalmia, aniridia, other anterior nent, making certain individuals more vul- chamber developmental anomalies, or reti- nerable to the environmental insults. nal degenerations. Cataracts may also be Author Affiliations: Department of Ophthalmology and Visual Sciences, part of multisystem genetic disorders, such Washington University School of Medicine, St Louis, Mo (Dr Shiels); Ophthalmic as chromosome abnormalities, Lowe syn- Genetics and Visual Function Branch, National Eye Institute, National Institutes drome, or neurofibromatosis type 2. In of Health, Bethesda, Md (Dr Hejtmancik). some cases this distinction is blurred. In-

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 165

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 herited cataracts may be isolated in tural proteins in the lens and in hu- son with age-related cataracts, which some individuals and associated with mans comprise 3 major classes are responsible for blinding 17 mil- additional findings in others, as in encoded by multiple genes, the ␣-, lion persons, causing just less than the developmental abnormality an- ␤-, and ␥-crystallins. As the ␤- and half of all blindness worldwide.11 terior segment mesenchymal dys- ␥-crystallins slowly accumulate dam- Cataracts are the leading cause of low genesis, resulting from abnormali- age over the lifetime of an indi- vision in the United States,11 and ties in the PITX3 gene.6 vidual, they lose the ability to par- cataract surgery is the most fre- Hereditary mendelian cataracts ticipate in normal intermolecular quently performed surgical proce- may be inherited as autosomal domi- interactions, and even to remain in dure in the United States, under- nant (most frequent), autosomal re- solution. As these crystallins begin gone by about 5% of the American cessive, or X-linked traits. Pheno- to denature (lose their native struc- population older than 40 years. Be- typically identical cataracts can result ture) and precipitate (come out of cause of its demographics, it has from mutations at different genetic solution), they are bound by the been estimated that delaying the de- loci and may have different inheri- ␣-crystallins, which have a chaper- velopment of cataract by 10 years tance patterns, while phenotypi- onelike activity.9 That is, binding by would decrease the need for cata- cally variable cataracts can be found ␣-crystallins maintains solubility of ract surgery by about 45%.12 Age- in a single large family.2 There are sev- ␤␥-crystallins and reduces light scat- related cataract is associated with a eral classification systems that have tering, but in general, the ␣-crystal- number of environmental risk fac- been developed based on the ana- lins appear not to renature their tar- tors, including cigarette smoking or tomical location of the opacity. In an get proteins and release them into chronic exposure to wood smoke, attempt to deal with congenital cata- the cytoplasm, as do true chaper- obesity or elevated blood glucose lev- ract, Merin and Crawford7 have pro- ones. Rather, they hold them in com- els, poor infantile growth, expo- posed a system based on morpho- plexes that, while soluble, increase sure to UV light, and alcohol con- logical classification. Summarized in size as additional damaged pro- sumption.13 Conversely, antioxidant very briefly, the cataract is classified tein is bound over time until they vitamins seem to have a protective as total (mature or complete), polar themselves begin to approach sizes effect, although this has not been (anterior or posterior), zonular sufficient to scatter light.9 Eventu- borne out by all studies.14 (nuclear, lamellar, or sutural), and ally, the available ␣-crystallin is over- Epidemiological evidence sup- capsular or membranous. whelmed by increasing amounts of ports the importance of genetic modified ␤␥-crystallin and the com- factors in the pathogenesis of age- AGE-RELATED CATARACT plexes precipitate within the lens related cataract.15,16 The Lens Opaci- cell, forming the insoluble protein ties Case-Control Study17 and the In age-related cataracts, the lens is fraction that is known to increase Italian-American Cataract Study clear during infancy and remains with age and in cataractous lenses. Group16 support a role for family his- clear until sometime after 45 years Whether proteins in the insoluble tory as a risk factor in cortical, mixed of age when progressive opacities be- fraction become insoluble on com- nuclear and cortical, and posterior gin to form in the lens. These opaci- plete or partial denaturation, as subcapsular cataracts. The Framing- ties almost certainly result at least in would be implied by the schema de- ham Offspring Eye Study18 showed part from the cumulative damage of scribed earlier, or whether they sim- that individuals with an affected sib- environmental insults on lens pro- ply become less soluble because of ling have a 3-fold increased risk of teins and cells. Lens proteins are modifications that leave their pro- having a cataract. The Beaver Dam known to undergo a wide variety of tein folds largely intact is not known Eye Study19 suggested that a single alterations with age, and many of currently. However, it seems clear major gene could account for as these are accelerated in the pres- from numerous mouse models of much as 35% of nuclear and up to ence of oxidative, osmotic, or other cataract that the presence of large 75% of cortical cataract variability. stresses. These stresses are them- amounts of unstable or precipi- The twin eye study20 demonstrated selves known to be associated with tated protein does damage to the lens a significant genetic influence on cataracts. In the case of lens crystal- cell and contributes to cataracts not age-related cataract, with heritabil- lins, these include proteolysis, an in- only directly through light scatter- ity accounting for 53% to 58% of the crease in disulfide bridges, deami- ing by protein aggregates but even- liability for cortical cataract and 48% dation of asparagine and glutamine tually also through disruption of of the risk for nuclear cataract. residues, racemization of aspartic cellular architecture.10 Similarly, mu- acid residues, phosphorylation, non- tations that disrupt intracellular ho- CURRENT APPROACHES enzymatic glycosylation, and carba- meostasis of lens cells can damage AND TOOLS mylation. Many of these changes their constituents over time and con- have been found to be increased in tribute to age-related cataract, as dis- Genetic causes of congenital cata- cataractous lenses and to be in- cussed later for galactokinase. racts have been identified by a com- duced in vitro or in model systems While congenital cataracts can be bination of linkage analysis and by the same stresses epidemiologi- particularly threatening to vision and screening candidate genes for mu- cally associated with cataracts.8 up to one half of all congenital cata- tations. Linkage analysis, a power- As a possible example, crystal- racts are inherited, they affect rela- ful tool to sort out the different ge- lins are the major soluble struc- tively few individuals in compari- netic loci that can cause human

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 166

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 cataracts, localizes mutant genes 8 are associated with additional ab- cessive cataracts, which are associ- causing inherited cataracts to a spe- normalities, mostly as part of devel- ated with a chain termination muta- cific chromosomal region by com- opmental syndromes. These tend to tion near the beginning of the paring their inheritance patterns result from mutations in genes en- protein,26 and in autosomal domi- with those of known genetic mark- coding transcriptional activators, and nant cataracts, which are associated ers. Most cataract loci currently have most of these have been identified with nonconservative missense mu- been identified using microsatellite by sequencing candidate genes in pa- tations.27 The chain termination mu- markers, although single nucleo- tients with developmental anoma- tation would be expected to cause loss tide polymorphisms (SNPs) are rap- lies. Two notable exceptions are the of function of the mutant protein idly gaining favor. Both ap- ␣B-crystallin gene, mutations in without affecting protein synthe- proaches remain useful. New which can cause either isolated cata- sized from the normal gene, suggest- analytical approaches using homo- racts or cataracts associated with my- ing that half the normal levels of zygosity mapping methods to iden- opathy, and the ferritin gene, which ␣-crystallin can provide sufficient tify genomic regions identical by de- causes the hyperferritinemia- chaperonelike activity and struc- scent promise to be increasingly cataract syndrome (Table). While in tural crystallin packing to establish useful in studying rare autosomal some cases (eg, some ␣- and ␤-crys- and maintain lens transparency. recessive cataracts from isolated tallin mutations) inherited congen- These findings are consistent with populations. While it has been es- ital cataracts are associated with mi- data from knockout mice in which the timated that there are 30 autoso- crocornea and even microphakia, ␣A-crystallin gene is disrupted. In mal dominant congenital cataract with the exception of heat shock these mice, the lenses are somewhat loci in man,21 the number of iden- transcription factor 4 (HSF4), most smaller in size and develop cataracts tified loci is currently approaching inherited cataracts caused by muta- associated with the presence of in- that (Table), with no obvious sign tions in growth or transcription fac- clusion bodies containing ␣B- of plateauing. Obviously, much work tors are associated with extralen- crystallin.28 The occurrence of domi- remains to be done in understand- ticular abnormalities. nant cataracts with the missense ing inherited congenital cataracts. Of the mapped loci for isolated mutations suggests that the mutant Age-related cataract loci gener- congenital or infantile cataracts, ␣A-crystallin protein exerts a delete- ally have been studied using a com- more than 20 have been associated rious effect that actively damages the bination of model-based and model- with mutations in specific genes. Of lens cell or its constituent proteins, free linkage analysis and association the families with cataract for whom or inhibits the function of the re- studies. Because the late age at on- the mutant gene is known, about half maining normal ␣-crystallin, rather set often precludes studying mul- have mutations in crystallins and than acting through loss of chaper- tiple generations of a single family, about a quarter have mutations in one function as the recessive cata- the cataracts are often variable in se- connexins, with the remainder ract appears to do. verity and even appearance, and the largely split between the genes for Because ␣A- and ␣B-crystallins mode of inheritance is complex, age- HSF4, aquaporin 0 (AQP0, MIP), and are found in the lens associated into related cataracts are significantly beaded filament structural protein 2 large multimeric complexes and more difficult to study than congen- (BFSP2). Inheritance of the same function similarly in vitro, one might ital cataracts. However, progress is mutation in different families or even expect that mutations in ␣B- beginning to be made by associa- the same mutation within the same crystallin would have a similar effect tion studies on candidate genes and family can result in radically differ- to those in ␣A-crystallin, at least in model-free linkage analysis, as de- ent cataract morphologies and se- the lens. However, the first human scribed later. verities. This suggests that addi- mutation reported in ␣B-crystallin tional genes or environmental factors was associated with desmin-related OVERVIEW OF CATARACT might modify the expression of the myopathy and only “discrete” cata- GENETICS primary mutation associated with racts.29 This was a missense muta- the cataracts. Conversely, cataracts tion that reduced ␣B-crystallin chap- Congenital Cataract with similar or identical clinical erone activity dramatically, causing manifestations can result from mu- aggregation and precipitation of the Cataracts can be isolated or can oc- tations in quite different genes. protein under stress. The myopa- cur in association with a large num- thy associated with this mutation is ber of metabolic diseases and ge- Specific Genes Implicated probably related to the expression of netic syndromes.2 Isolated congenital in Congenital Cataracts ␣B-crystallin, but not ␣A-crystal- cataracts tend to be highly pen- lin, in muscle cells, where it binds etrant mendelian traits, with auto- Examination of the genes impli- and presumably stabilizes des- somal dominant more common than cated in congenital cataracts pro- min.30 Similarly, an ␣B-crystallin autosomal recessive cataracts. Cur- vides insight into those biological knockout mouse exhibits myopa- rently, as listed in the Table, there pathways important for lens trans- thy without cataracts.30 In contrast, are about 34 genetic loci to which parency and homeostasis as well as a deletion in the ␣B-crystallin gene isolated or primary cataracts have being of some clinical interest. Mu- resulting in a frameshift and expres- been mapped, although the num- tations in the ␣A-crystallin gene have sion of an aberrant 184 amino ber is constantly increasing. Of these, been implicated both in autosomal re- acid protein causes autosomal

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 167

Locus/Gene DNA Protein Mode of Associated Chromosome (MIM) Change Change Inheritance Cataract Phenotype Phenotype 1p36 CCV (115665) AD Progressive lamellar CTPP1 (116600) AD Posterior polar 22* AD Total 1p32 FOXE3 (601094) c.943insC AD Anterior polar? Anterior segment ocular dysgenesis 1p13.3 GSTM1 (138350) Null C Age-related ( Japanese, Iranian) None C Age-related cortical (Estonian) 1q21.1 GJA8 (600897) c.G68C p.R23T AD Nuclear c.T131A p.V44E AD Total Microcornea, mild myopia c.G142A p.E48K AD Zonular nuclear pulverulent c.T191G p.V64G AD Nuclear c.C262T p.P88S AD Zonular pulverulent c.C262A p.P88Q AD Lamellar pulverulent c.G593A p.R198Q AD Posterior subcapsular Microcornea, mild myopia c.T741G p.I247M AD Zonular pulverulent 2p24-pter 23* AD Coralliform 2p12 CNNP (607304) AD Nuclear 2q33-q35 CRYGC (123680) c.A13C p.T5P AD Central zonular pulverulent c.123-124ins5bp p.C42fs AD Variable zonular pulverulent c.C502T p.R168W AD Lamellar CRYGD (123690) c.C43T p.R14/15C AD Punctate AD Nuclear coralliform punctate High myopia c.C70A p.P23/24T AD Lamellar AD Cerulean AD Flaky silicalike nuclear AD Coral-like AD Fasciculiform c.C109A p.R36/37S AD Crystal-like AD Nuclear golden crystal c.G176A p.R58/59H AD Aculeiform c.G470A p.W156/157X AD Central nuclear CCP (603212) AD Polymorphic 3p21.3-p22.3 24* AR ? 3q21-q22 BFSP2 (603212) c.697_699delGAA p.E233del AD Nuclear sutural stellate AD Y-sutural Myopia c.859CϾT p.R287W AD Nuclear sutural lamellar 3q25-qter CRYGS (123730) c.G53T p.G18V AD Cortical progressive 6p24 GCNT2 (600429) c.G983A W328X AR ? Adult i blood group 6p12-q12 ARCC1 (609026) C Age-related cortical 8q13.3 EYA1 (601653) p.R514G AD Nuclear type Central corneal opacity, Peters anomaly p.G393S AD Nuclear type BOR 9q13-q22 CAAR (605749) AR Adult-onset cortical pulverulent, progressive nuclear, and posterior subcapsular AR ?Congenital 10q25 PITX3 (602669) c.G38A p.S13N AD Total c.650delG AD Progressive posterior polar c.656-657ins17bp AD Anterior cortical ASMD, optic nerve defects AD Posterior polar ASMD AD Posterior polar ASMD AD Progressive posterior polar AD Progressive posterior polar AD Posterior polar 11p13 PAX6 (607108) c.C1058G S353X AD? Lamellar anterior capsular, posterior Corneal dystrophy subcapsular g.IVS4a-3TϾC AD? Cortical equatorial, progressive Peripheral corneal posterior polar opacity, glaucoma, nystagmus

(continued)

dominant cataracts in the absence of associated cataract, with the aber- Most mutations described in the myopathy.31 This seems more simi- rant protein likely to have a toxic ␤␥-crystallins would be expected to lar to the dominant ␣A-crystallin– effect on the lens cells. cause major abnormalities in the

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 168

Locus/Gene DNA Protein Mode of Associated Chromosome (MIM) Change Change Inheritance Cataract Phenotype Phenotype 11q22.1-q23.2 CRYAB (123590) c.A358G p.R120G AD “Discrete” Myopathy c.G418A p.D140N AD Lamellar c.450delA p.K150fs AD Posterior polar 12q13-q14 MIP (154050) c.A401G p.E134G AD Lamellar sutural c.C413G p.T138R AD Progressive punctate polymorphic c.638delG p.G213fs AD Punctate 13q11-q12 GJA3 (121015) c.G82A p.V28M AD Variable total c.C96A p.F32L AD Nuclear pulverulent c.G134C p.W45S AD Nuclear c.C176T p.P59L AD Nuclear punctate c.A188G p.N63S AD Variable pulverulent c.G226A p.R76H AD Nuclear lamellar pulverulent c.C226G p.R76G AD Total c.C560T p.P187L AD Zonular pulverulent c.A563C p.N188T AD Nuclear pulverulent c.1137insC p.S380fs AD Punctate 14q24.3 CHX10 (142993) c.G599A/C p.R200Q/P AR ? Microphthalmia, iris coloboma, dislocated lens 15q21-q22 CCSSO (605728) AD Central saccular sutural 16q22.12 HSF4 (602438) c.C59A p.A20D AD ? c.A559G p.I87V AD Cortical lamellar c.T344C p.L115P AD Lamellar c.C358T p.R120C AD Zonular stellate, anterior polar (Marner) c.G524C p.R175/176P AR Nuclear and cortical c.595-599del5bp AR ? g.IVS12 ϩ 4AϾG AR Total 16q22-q23 MAF (177075) t(5;16) Cortical pulverulent sutural, Peters anomaly progressive posterior subcapsular c.G863C p.R288P AD Cortical (lamellar) nuclear Microcornea, iris pulverulent coloboma 17p13-p12 CTAA2 (601202) AD Anterior polar 17q11.2-q12 CRYBA3/A1 (123610) g.IVS3 ϩ 1GϾA AD Zonular sutural AD Sutural nuclear cortical g.IVS3 ϩ 1GϾC AD Pulverulent nuclear sutural c.271-273del3bp p.G91del AD Nuclear AD Nuclear suture-sparing AD Lamellar 17q24 GALK1 (604313) c.C293T p.A198V ? Age-related (Asian) 17q24 CCA1 (115660) AD Cerulean 19q13 25* AR Nuclear 19q13.4 FTL (134790) IRE† AD Nuclear cortical breadcrumblike Hyperferritinemia- cataract syndrome 19q13.4 LIM2 (154045) c.T313G p.F105V AR Pulverulent cortical sutural 20p12-q12 CTPP3 (605387) AD Posterior polar 21q22.3 CRYAA (123580) c.G27A p.W9X AR ? c.C145T p.R49C AD Central nuclear c.C346T p.R116C AD Zonular central nuclear, cortical, Microcornea, posterior subcapsular microphthalmia AD Fan-shaped Microcornea 22q11.2 CRYBB1 (600929) c.G658T p.G220X AD Central sutural pulverulent c.T757C p.X253R AD Nuclear cortical riders Microcornea CRYBB (123620) c.C463T p.Q155X AD Cerulean AD Central zonular pulverulent AD Sutural cerulean AD Progressive polymorphic c.G453T p.W151C AD Central nuclear CRYBB3 (123630) c.G493C p.G165R AR Nuclear cortical riders CRYBA4 (123631) c.T242C p.L69P AD Congenital lamellar Microphthalmia Xp22 CXN (NHS?) (300457) XL Fan-shaped nuclear Cardiac anomalies

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ASMD, anterior segment mesenchymal dysgenesis; BOR, branchiootorenal dysplasia syndrome; bp, base pair; C, complex; fs, frameshift; IRE, iron response element; MIM, Mendelian Inheritance in Man number; XL, X-linked; ?, morphology of the cataract is in doubt. *This cataract is not listed in Online MIM and thus is independently referenced. †Mutations located in the 5Ј IRE.

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 169

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 protein structure, presumably re- chain) levels in the lens can in- Lamellar and polymorphic cata- sulting in an unstable protein that crease dramatically to levels ap- racts have been associated with mis- precipitates from solution and serves proaching that of a crystallin. The sense mutations in the AQP0 (MIP) as a nidus for additional protein molecular pathology lies in the fer- gene. One mutation, E134G, is as- denaturation and precipitation, ritin L iron-responsive element, a sociated with a nonprogressive con- eventually resulting in cataract for- stem loop structure in the 5Ј un- genital lamellar cataract, and the sec- mation. These include missense mu- translated region of the ferritin mes- ond, T138R, is associated with tations, insertions changing the read- senger RNA. Normally, this struc- multifocal opacities that increase in ing frame and causing expression of ture binds a cytoplasmic protein, the severity throughout life. Both of aberrant peptides with premature iron regulatory protein, which then these mutations appear to act by in- termination, and splice mutations, inhibits translation of ferritin mes- terfering with normal trafficking of as presented in the Table. Although senger RNA. Mutation of this struc- AQP0 to the plasma membrane and phenotypes can vary significantly, ture and overexpression of ferritin thus with water channel activity.36 mutations in ␥-crystallins tend to pro- by loss of translational control in the In addition, both mutant proteins duce nuclear or zonular cataracts, hyperferritinemia-cataract syn- appear to interfere with water chan- consistent with their high level of ex- drome results in crystallization of nel activity by normal AQP0, con- pression in the lens nucleus. Presum- ferritin in the lens, similar to that de- sistent with a dominant negative ably, central nuclear cataracts reflect scribed earlier for the R36S and mechanism for the autosomal domi- high-level expression of the mutant R58H ␥-crystallin mutations, and the nant inheritance of the cataracts. gene early in lens development, while appearance of bread crumb–like Beaded filaments are a type of in- zonular cataracts reflect synthesis opacities in the cortex and nucleus. termediate filament unique to the somewhat later and for a limited pe- This emphasizes the requirement lens fiber cells. They are made up of riod, resulting in a shell of opaque that crystallins or other proteins BFSP1 (also called CP115 or filen- cells surrounded internally and ex- must be exceptionally soluble to be sin) and BFSP2 (also called CP49 or ternally by relatively clear lens. The expressed at such high levels in the phakinin), highly divergent inter- cataract phenotypes reported with lens without causing dysfunction. mediate filament proteins that com- mutations in the ␤-crystallins are Connexins 46 and 50 are con- bine in the presence of ␣-crystallin somewhat more varied, ranging in dif- stituents of gap junctions, on which to form the appropriate beaded ferent families from zonular pulveru- the avascular lens depends for nu- structure. Cataracts in 3 families lent with or without involvement of trition and intercellular communi- have been associated with muta- the sutures to cerulean cataracts. The cation. At least 1 cataract-associ- tions in BFSP2. In 1 family, the cata- association of identical mutations in ated mutation in the connexin 50 racts were associated with a non- ␤B2-crystallin in different families gene, the P88S missense mutation in conservative missense mutation in with nuclear lamellar Coppock-like the second transmembrane do- exon 4 substituting a tryptophan for and cerulean cataracts emphasizes main, has been shown to result in a an evolutionarily conserved argi- the importance of modifying genes connexin that fails to form func- nine in the central rod domain of the in the phenotypic expression of these tional gap junctional channels. In- protein.37 A deletion resulting in the mutations. corporation of even a single mu- loss of Glu233 in this protein has Recently, 2 mutations in ␥D- tant protein molecule into a gap also been associated with cata- crystallin, R36S and R58H, have junction in Xenopus oocytes inhib- racts.38 These cataracts are nuclear been shown not to alter the protein its channel function.34 Mutant con- or nuclear lamellar, with some in- fold, but rather to alter the surface nexin 46 proteins are also associ- volvement of the sutures, consis- characteristics of the protein.32 This, ated with cataracts. Two mutant tent with fiber cell–specific expres- in turn, lowers the solubility and en- connexins, with an N63S missense sion of the beaded filament proteins. hances the crystal nucleation rate of mutation in the first extracellular do- HSF4 is a member of the heat- these mutants so that they precipi- main and a frameshift mutation at shock transcription factor family, tate out of solution, in at least 1 case residue 380, which causes read- which regulates expression of heat- actually forming crystals in the lens. through into the 3Ј untranslated re- shock proteins, including lens ␣B- In a third mutation in ␥D-crystal- gion until an in-frame stop codon 90 crystallin,39 in response to elevated lin, R14C, the protein also main- nucleotides downstream from the temperature and other stress stimuli tains a normal protein fold but is wild-type stop codon, also fail to (eg, oxidation). Mutations in HSF4 susceptible to thiol-mediated aggre- form intercellular channels in paired have been associated with autoso- gation.33 These results emphasize Xenopus oocytes.35 However, these mal dominant and recessive cata- that crystallins need not undergo mutant connexins are unable to par- racts. The dominant cataracts were denaturation or other major changes ticipate in gap junction formation at initially seen in early childhood and in their protein folds to cause all and thus do not inhibit channel were described as lamellar,40 includ- cataracts. function by products of the normal ing the historically important Marner The hyperferritinemia-cataract gene. Mutations in both connexin 46 cataract family,41 whereas the reces- syndrome is a recently described dis- and connexin 50 produce pheno- sive cataracts had a congenital onset order in which cataracts are associ- typically similar autosomal domi- and ranged in severity from nuclear ated with hyperferritinemia with- nant nuclear and especially zonu- with some cortical involvement42 to out iron overload. Ferritin L (light lar pulverulent cataracts. total lens opacities.43 Interestingly, the

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 170

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 dominant mutations in HSF4 lie and cataract.45 Intriguingly, this frequency occurs in 4.1% of Japa- within the ␣-helical DNA-binding do- novel cataract locus maps close to a nese individuals overall and 7.1% of main, whereas the recessive muta- susceptibility locus for diabetic reti- Japanese individuals with cata- tions lie outside this highly con- nopathy46 associated with type 2 dia- racts. The allele was also present in served functional domain. betes mellitus (Online Mendelian In- 2.8% of Korean individuals but had heritance in Man 125853), a known a lower incidence in Chinese indi- Age-Related Cataract risk factor for age-related cortical viduals and was not seen in black or cataract. The 1p interval (approxi- white individuals from the United Linkage Studies. In addition to epi- mately 26 megabase pairs) con- States. This and other GALK1 vari- demiological evidence implicating tains approximately 400 positional ants appeared to be absent from genetic factors in age-related cata- candidate genes and likely includes northern Italian individuals with ract, a number of inherited cata- the loci for Volkman cataract,47 pos- age-related cataract, suggesting that racts with postinfantile age at onset terior polar cataract,48 and total cata- the genetic contributions to cata- or progression of the opacity ract.22 The potential susceptibility ract might vary in different popula- throughout life have been de- loci on 1q31 and 2q33 lie near the tions. However, decreased activity of scribed. Mutations in BFSP2 can connexin 50 gene and the ␥-crys- galactokinase consistent with het- cause juvenile cataracts, the Marner tallin gene cluster, respectively, sug- erozygous deficiency was found in and Volkmann cataracts can be pro- gesting the possibility that genes 3 of 39 white subjects, confirming gressive, mutations in AQP0(MIP) linked with autosomal dominant the importance of galactokinase ac- and ␥C-crystallin can cause progres- congenital cataracts may also con- tivity for maintenance of lens trans- sive cataracts, and the CAAR locus tribute to age-related cataract. The parency over time.51,52 Similar re- is linked to familial adult-onset pul- difficulties in carrying out linkage sults were also seen for galactose verulent cataracts. These all sug- studies of age-related cataracts are 1-phosphate uridyltransferase activ- gest that for at least some genes, a reflected in the multiple chromo- ity in 3 of 45 subjects.52 mutation that severely disrupts the somal regions possibly implicated, The GALK1 results fit in well with protein or inhibits its function might in the relatively low likelihood that the known influence of hyperglyce- result in congenital cataracts inher- each one is significant, and in the mia on age-related cataract, prob- ited in a highly penetrant mende- large sizes of most of the regions and ably with an oxidative component. lian fashion, while a mutation that the correspondingly large numbers That these cataracts result from causes less severe damage to the of genes they contain. polyol accumulation is suggested by same protein or impairs its func- work in galactosemic dogs and trans- tion only mildly might contribute to Association Studies. Galactosemic genic and knockout mice.53 Dogs age-related cataracts in a more com- cataracts provide an interesting ex- have aldose reductase levels simi- plex multifactorial fashion. Simi- ample of mutations severely affect- lar to those in humans and when larly, mutations that severely dis- ing a gene, causing early-onset cata- made hyperglycemic readily de- rupt the lens cell architecture or racts, while milder mutations simply velop sugar cataracts that are pre- environment might produce con- decreasing its activity contribute to vented by aldose reductase inhibi- genital cataracts, while others that age-related cataracts.49 Deficien- tors. Mice, which have very low cause relatively mild disruption of cies of galactokinase (GALK1) and aldose reductase activity in the lens, lens cell homeostasis might contrib- galactose 1-phosphate uridyltrans- are naturally resistant to sugar cata- ute to age-related cataract. ferase and severe deficiencies of uri- racts, either galactosemic or hyper- In contrast to congenital cata- dine diphosphate 1-4 epimerase glycemic. However, on transgenic racts, mapping and identification of cause cataracts as a result of galac- expression of aldose reductase, mice genes for age-related cataract is still titol accumulation and subsequent readily develop cataracts, espe- in its infancy. The first genome- osmotic swelling. The latter 2 are cially when the galactokinase or sor- wide scan, using model-free link- also associated with vomiting, fail- bitol dehydrogenase gene is de- age analysis of affected sib pairs, has ure to thrive, liver disease, and men- leted. Consistent with these animal recently identified a number of ma- tal retardation, if untreated, while the data are the recent findings that sus- jor and minor susceptibility loci for cataracts in galactokinase defi- ceptibility to cataracts as a diabetic age-related cortical cataract in white ciency are isolated. Interestingly, ga- complication in humans is associ- individuals.44 The most statistically lactosemic cataracts initially are re- ated with specific allele Z of the mi- significant loci were found on chro- versible both in human patients and crosatellite polymorphism at the 5Ј mosomes 6p12-q12 and 1p, with up in animal models. In 2001, a novel end of the aldose reductase gene.53 to 10 suggested loci on 8 other chro- variant of galactokinase, the “Osaka” mosomes including 1q31 and 2q33. variant with an A198V substitu- CLINICAL IMPLICATIONS The 6p12-6q12 genetic interval tion, was shown to be associated AND GENETIC COUNSELING spanning the centromere (approxi- with a significant increase in bilat- mately 60 centimorgans) contains eral cataracts in adults.50 It results in Congenital cataracts can lead to per- more than 260 positional candi- instability of the mutant protein and manent blindness by interfering with date genes excluding GCNT2, which is responsible for mild galactoki- the sharp focus of light on the retina has been associated with the reces- nase deficiency, leaving about 20% and resulting in failure to establish sive adult i blood group phenotype of normal levels. This variant allele appropriate visual cortical synaptic

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 171

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 connections with the retina. Prompt Differential Diagnosis is important and surgery may be diagnosis and treatment can pre- and Diagnostic Tests required, the timing and necessity vent this. Understanding the biol- providing perhaps the most diffi- ogy of the lens and the pathophysi- The differential diagnosis of a he- cult aspect of caring for congenital ology of selected types of cataract can reditary congenital cataract in- cataracts. yield insight into the process of cata- cludes (1) Prenatal causes includ- Studies begun in kittens56 and ractogenesis in general and provide ing virus or other infectious disease; extended to nonhuman pri- a framework for the clinical ap- this is more common in developing mates57,58 show that unequal input proach to diagnosis and therapy. countries. Rubella directly involves into cortical neurons due to unilat- the lens, whereas other infectious eral form deprivation results in Evaluation agents (toxoplasmosis, mumps, more severe visual deficits than measles, influenza, chickenpox, her- does bilateral deprivation. Thus, After establishing the significance and pes simplex, herpes zoster, cyto- ophthalmic surgeons generally con- classifying the cataract by type, the megalovirus, and echovirus type 3) sider a unilateral, dense congenital evaluation of a cataract consists of a result in ocular inflammation (uve- cataract to be a surgical emergency, careful assessment of its effect on the itis). Depending on the clinical set- while bilateral, dense cataracts can vision and function. The first assess- ting, these can be screened for by a be scheduled in a more routine ment in small children (0-3 years of variety of cultures and other tests in- fashion. Usual practice suggests age) is usually carried out by obser- cluding TORCH (toxoplasmosis, that limited dense cataracts can be vation fixing and following and by other agents, rubella, cytomegalo- operated on successfully in the first covering alternate eyes and observ- virus, herpes simplex) titers. (2) De- weeks of life, while bilateral cata- ing the response. Covering the eye velopmental abnormalities associ- racts can be operated on success- with good vision will cause more fret- ated with prematurity. These may be fully up to 3 months of age. With ting, objecting, and crying. More ac- associated with low birth weight, prompt surgery, the visual progno- curate assessment is provided by spe- birth anoxia, or central nervous sys- sis is better for bilateral as com- cialized testing including visually tem involvement leading to sei- pared with unilateral cases and in evoked cortical responses, preferen- zures, cerebral palsy or hemiplegia, less dense cataracts as compared tial looking, or the forced-choice and retinopathy of prematurity. (3) with total opacities. When congeni- method.54,55 With older children, sub- Perinatal-postnatal problems, such tal cataracts are associated with jective tests, including identifica- as hyperglycemia and hypocalce- other ocular abnormalities and/or tion of the illiterate E or Allen cards mia, can cause cataracts. These are systemic disease, a poorer visual (picture-differentiating tests), are associated with signs of diabetes and outcome often results.59-61 Lastly, used. Finally, once the alphabet is tetany, respectively, and can be communication between health learned, conventional acuity testing screened for by serum chemistries. care professionals, therapists, and by a log minimum angle of resolu- (4) Association with other ocular teachers combined with counseling tion Early Treatment of Diabetic Reti- abnormalities, including anterior of patients is very important in the nopathy Study or Snellen chart may chamber abnormalities (eg, Reiger treatment of young patients with be used. syndrome or anomaly, primary hy- cataract and their families.62 Cataracts may be visualized in a perplastic vitreous, aniridia, reti- variety of ways. When viewed with nopathies such as retinal dysplasia, Accepted for Publication: Septem- a hand light, a cataract may appear Norrie disease, and microphthal- ber 20, 2006. as white pupillary opacity (leukoco- mia). (5) Association with multisys- Correspondence: J. Fielding ria). Direct ophthalmoscopy is use- tem syndromes may be suggested by Hejtmancik, MD, PhD, Ophthal- ful to evaluate the effect on visual the results of clinical examination, mic Genetics and Visual Function function following the principle that chromosome analysis, and specific Branch, National Eye Institute, if the examiner can see the optic nerve blood and urine chemistries, deter- National Institutes of Health, and macula, the patient can prob- mined by which syndromes are Bethesda, MD 20892-1860 (f3h ably see out. One can visualize a lens suspected. @helix.nih.gov). opacity silhouetted in the red reflex Financial Disclosure: None re- using either direct illumination or ret- Treatment ported. roillumination. The definitive de- scription of a lens opacity depends on When unilateral and bilateral cata- a slitlamp biomicroscopic examina- racts are thought to reduce vision REFERENCES tion through a widely dilated pupil, significantly, management should allowing for direct illumination and include early diagnosis with 1. Benedek GB. Theory of transparency of the eye. Appl Opt. 1971;10:459-473. retroillumination with appropriate prompt evaluation to identify etiol- 2. Hejtmancik JF, Kaiser-Kupfer MI, Piatigorsky J. magnification to visualize the lens ogy when possible. Galactosemia Molecular biology and inherited disorders of the opacity and define its clinical fea- is an example in which rapid diag- eye lens. In: Scriver CR, Beaudet AL, Valle D, et tures. Photographs are useful to nosis and treatment will permit al, eds. The Metabolic and Molecular Basis of In- herited Disease. 8th ed. New York, NY: McGraw document the features and progres- recovery of the lens to a normal Hill; 2001:6033-6062. sion of the cataract, especially in a re- state of clarity. Determination of 3. Hejtmancik JF, Smaoui N. Molecular genetics of search setting. the extent of compromise in vision cataract. In: Wissinger B, Kohl S, Langenbeck U,

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 172

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 eds. Genetics in Ophthalmology. Basel, Switzer- A nonsense mutation (W9X) in CRYAA causes au- mozygous splice mutation in the HSF4 gene is as- land: S Karger; 2003:67-82. tosomal recessive cataract in an inbred Jewish Per- sociated with an autosomal recessive congenital 4. Francois J. Genetics of cataract. Ophthalmologica. sian family. Invest Ophthalmol Vis Sci. 2000; cataract. Invest Ophthalmol Vis Sci. 2004;45: 1982;184:61-71. 41:3511-3515. 2716-2721. 5. Merin S. Inherited cataracts. In: Merin S, ed. In- 27. Litt M, Kramer P, LaMorticella DM, Murphey W, 44. Iyengar SK, Klein BE, Klein R, et al. Identification of herited Eye Diseases. New York, NY: Marcel Dek- Lovrien EW, Weleber RG. Autosomal dominant amajorlocusforage-relatedcorticalcataractonchro- ker Inc; 1991:86-120. congenital cataract associated with a missense mosome6p12-q12intheBeaverDamEyeStudy.Proc 6. Semina EV, Ferrell RE, Mintz-Hittner HA, et al. mutation in the human alpha crystallin gene NatlAcadSciUSA. 2004;101:14485-14490. A novel homeobox gene PITX3 is mutated in fami- CRYAA. Hum Mol Genet. 1998;7:471-474. 45. Pras E, Raz J, Yahalom V, et al. A nonsense mu- lies with autosomal-dominant cataracts and ASMD. 28. BradyJP,GarlandD,Duglas-TaborY,RobisonWGJr, tation in the glucosaminyl (N-acetyl) transferase Nat Genet. 1998;19:167-170. Groome A, Wawrousek EF. Targeted disruption of 2 gene (GCNT2): association with autosomal re- 7. Merin S, Crawford JS. The etiology of congenital the mouse alpha A-crystallin gene induces cataract cessive congenital cataracts. Invest Ophthalmol cataracts: a survey of 386 cases. Can J Ophthalmol. andcytoplasmicinclusionbodiescontainingthesmall Vis Sci. 2004;45:1940-1945. 1971;6:178-182. heat shock protein alpha B-crystallin. Proc Natl Acad 46. Awata T, Inoue K, Kurihara S, et al. A common poly- 8. Ottonello S, Foroni C, Carta A, Petrucco S, Mara- SciUSA. 1997;94:884-889. morphism in the 5Ј-untranslated region of the VEGF ini G. Oxidative stress and age-related cataract. 29. Vicart P, Caron A, Guicheney P, et al. A missense gene is associated with diabetic retinopathy in type Ophthalmologica. 2000;214:78-85. mutation in the ␣B-crystallin chaperone gene 2 diabetes. Diabetes. 2002;51:1635-1639. 9. Rao PV, Huang QL, Horwitz J, Zigler JS Jr. Evi- causes a desmin-related myopathy. Nat Genet. 47. Eiberg H, Lund AM, Warburg M, Rosenberg T. dence that alpha-crystallin prevents non-specific 1998;20:92-95. Assignment of congenital cataract Volkmann type protein aggregation in the intact eye lens. Bio- 30. Brady JP, Garland DL, Green DE, Tamm ER, Gib- (CCV) to chromosome 1p36. Hum Genet. 1995; chim Biophys Acta. 1995;1245:439-447. lin FJ, Wawrousek EF. AlphaB-crystallin in lens de- 96:33-38. 10. Graw J. Congenital hereditary cataracts. Int J Dev velopment and muscle integrity: a gene knock- 48. Ionides AC, Berry V, Mackay DS, Moore AT, Bhat- Biol. 2004;48:1031-1044. out approach. Invest Ophthalmol Vis Sci. 2001; tacharya SS, Shiels A. A locus for autosomal domi- 11. Congdon NG, Friedman DS, Lietman T. Impor- 42:2924-2934. nant posterior polar cataract on chromosome 1p. tant causes of visual impairment in the world today. 31. Berry V, Francis P, Reddy MA, et al. Alpha-B crys- Hum Mol Genet. 1997;6:47-51. JAMA. 2003;290:2057-2060. tallin gene (CRYAB) mutation causes dominant 49. Skalka HW, Prchal JT. Presenile cataract forma- 12. Kupfer C. On presentation of the Friedenwald Award congenital posterior polar cataract in humans. Am tion and decreased activity of galactosemic of the Association for Research in Vision and Oph- J Hum Genet. 2001;69:1141-1145. enzymes. Arch Ophthalmol. 1980;98:269-273. thalmology to Dr Joram Piatigorsky. Invest Oph- 32. Pande A, Pande J, Asherie N, et al. Crystal cata- 50. Okano Y, Asada M, Fujimoto A, et al. A genetic fac- thalmol Vis Sci. 1987;28:2-8. racts: human genetic cataract caused by protein tor for age-related cataract: identification and char- 13. The Italian-American Cataract Study Group. Risk crystallization. Proc Natl Acad SciUSA. 2001; acterization of a novel galactokinase variant, factors for age-related cortical, nuclear, and pos- 98:6116-6120. “Osaka,” in Asians. Am J Hum Genet. 2001; terior subcapsular cataracts. Am J Epidemiol. 1991; 33. Pande A, Pande J, Asherie N, et al. Molecular basis 68:1036-1042. 133:541-553. of a progressive juvenile-onset hereditary cataract. 51. Stambolian D, Scarpino-Myers V, Eagle RC Jr, 14. West SK, Valmadrid CT. Epidemiology of risk fac- Proc Natl Acad Sci U S A. 2000;97:1993-1998. Hodes B, Harris H. Cataracts in patients hetero- tors for age-related cataract. Surv Ophthalmol. 34. Pal JD, Berthoud VM, Beyer EC, Mackay D, Shiels zygous for galactokinase deficiency. Invest Oph- 1995;39:323-334. A, Ebihara L. Molecular mechanism underlying a thalmol Vis Sci. 1986;27:429-433. 15. McCarty CA, Taylor HR. The genetics of cataract. Cx50-linked congenital cataract. Am J Physiol. 52. Stevens RE, Datiles MB, Srivastava SK, Ansari NH, Invest Ophthalmol Vis Sci. 2001;42:1677-1678. 1999;276:C1443-C1446. Maumenee AE, Stark WJ. Idiopathic presenile cata- 16. Risk factors for age-related cortical, nuclear, and 35. Pal JD, Liu X, Mackay D, et al. Connexin46 mu- ract formation and galactosaemia. Br J Ophthalmol. posterior subcapsular cataracts: the Italian- tations linked to congenital cataract show loss of 1989;73:48-51. American Cataract Study Group. Am J Epidemiol. gap junction channel function. Am J Physiol Cell 53. Lee AY, Chung SS. Contributions of polyol path- 1991;133:541-553. Physiol. 2000;279:C596-C602. way to oxidative stress in diabetic cataract. 17. Leske MC, Chylack LT Jr, Wu SY. The Lens Opaci- 36. Francis P, Chung JJ, Yasui M, et al. Functional im- FASEB J. 1999;13:23-30. ties Case-Control Study: risk factors for cataract. pairment of lens aquaporin in two families with 54. Dobson V, Teller DY. Visual acuity in human in- Arch Ophthalmol. 1991;109:244-251. dominantly inherited cataracts. Hum Mol Genet. fants: a review and comparison of behavioral and 18. Familial aggregation of lens opacities: the Framing- 2000;9:2329-2334. electrophysiological studies. Vision Res. 1978; ham Eye Study and the Framingham Offspring Eye 37. Conley YP, Erturk D, Keverline A, et al. A juvenile- 18:1469-1483. Study. Am J Epidemiol. 1994;140:555-564. onset, progressive cataract locus on chromo- 55. Atkinson J, Braddick O. Assessment of visual acu- 19. Klein BE, Klein R, Lee KE, Moore EL, Danforth L. some 3q21-q22 is associated with a missense mu- ity in infancy and early childhood. Acta Ophthal- Risk of incident age-related eye diseases in people tation in the beaded filament structural protein-2. mol Suppl. 1983;157:18-26. with an affected sibling: the Beaver Dam Eye Study. Am J Hum Genet. 2000;66:1426-1431. 56. Wiesel TN, Hubel DH. Comparison of the effects Am J Epidemiol. 2001;154:207-211. 38. Jakobs PM, Hess JF, FitzGerald PG, Kramer P, of unilateral and bilateral eyelid closure on corti- 20. Hammond CJ, Duncan DD, Snieder H, et al. The Weleber RG, Litt M. Autosomal-dominant con- cal responses in kittens. J Neurophysiol. 1965; heritability of age-related cortical cataract: the twin genital cataract associated with a deletion muta- 28:1029-1040. eye study. Invest Ophthalmol Vis Sci. 2001; tion in the human beaded filament protein gene 57. Harwerth RS, Smith EL III, Paul AD, Crawford ML, 42:601-605. BFSP2. Am J Hum Genet. 2000;66:1432-1436. von Noorden GK. Functional effects of bilateral form 21. Ehling UH. Genetic risk assessment. Annu Rev 39. Somasundaram T, Bhat SP. Developmentally dic- deprivation in monkeys. Invest Ophthalmol Vis Sci. Genet. 1991;25:255-280. tated expression of heat shock factors: exclusive ex- 1991;32:2311-2327. 22. McKay JD, Patterson B, Craig JE, et al. The telomere pression of HSF4 in the postnatal lens and its spe- 58. Robb RM, Mayer DL, Moore BD. Results of early of human chromosome 1p contains at least two in- cific interaction with alphaB-crystallin heat shock treatment of unilateral congenital cataracts. J Pe- dependent autosomal dominant congenital cataract promoter. JBiolChem. 2004;279:44497-44503. diatr Ophthalmol Strabismus. 1987;24:178-181. genes. Br J Ophthalmol. 2005;89:831-834. 40. Bu L, Jin YP, Shi YF, et al. Mutant DNA-binding 59. Nelson LB. Diagnosis and management of cata- 23. Gao L, Qin W, Cui H, et al. A novel locus of co- domain of HSF4 is associated with autosomal racts in infancy and childhood. Ophthalmic Surg. ralliform cataract mapped to chromosome dominant lamellar and Marner cataract. Nat Genet. 1984;15:688-697. 2p24-pter. J Hum Genet. 2005;50:305-310. 2002;31:276-278. 60. Moore AT. Understanding the molecular genet- 24. Pras E, Pras E, Bakhan T, et al. A gene causing 41. Eiberg H, Marner E, Rosenberg T, Mohr J. Marner’s ics of congenital cataract may have wider impli- autosomal recessive cataract maps to the short cataract (CAM) assigned to chromosome 16: cations for age related cataract. Br J Ophthalmol. arm of chromosome 3. Isr Med Assoc J. 2001; linkage to haptoglobin. Clin Genet. 1988;34: 2004;88:2-3. 3:559-562. 272-275. 61. Gelbart SS, Hoyt CS, Jastrebski G, Marg E. Long- 25. Riazuddin SA, Yasmeen A, Zhang Q, et al. A new 42. Forshew T, Johnson CA, Khaliq S, et al. Locus het- term visual results in bilateral congenital cataracts. locus for autosomal recessive nuclear cataract erogeneity in autosomal recessive congenital cata- Am J Ophthalmol. 1982;93:615-621. mapped to chromosome 19q13 in a Pakistani family. racts: linkage to 9q and germline HSF4 mutations. 62. Burns EC, Jones RB. Long term management of Invest Ophthalmol Vis Sci. 2005;46:623-626. Hum Genet. 2005;117:452-459. congenital cataracts. Arch Dis Child. 1985;60: 26. Pras E, Frydman M, Levy-Nissenbaum E, et al. 43. Smaoui N, Beltaief O, Benhamed S, et al. A ho- 322-325.

(REPRINTED) ARCH OPHTHALMOL / VOL 125, FEB 2007 WWW.ARCHOPHTHALMOL.COM 173