INVITED EDITORIAL The Genetics of Cataract: Our Vision Becomes Clearer

Abstract

The article by Shiels et al., 1998Shiels A Mackay D Ionides A Berry V Moore A Bhattacharya S A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant “zonular pulverulent” cataract, on chromosome 1q.Am J Hum Genet. 1998; 62 (in this issue): 526-532Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, describing a mutation in the human connexin50 gene (GJA8) in individuals with the autosomal dominant zonular pulverulent cataract (CAE1), represents a milestone for human genetics. The CAE1 locus was initially linked with the Duffy blood-group locus by Renwick and Lawler, 1963Renwick JH Lawler SD Probable linkage between a congenital cataract locus and the Duffy blood group locus.Ann Hum Genet. 1963; 27: 67-84Crossref PubMed Scopus (114) Google Scholar, and in 1968 the Duffy blood-group locus was assigned to chromosome 1 (Donahue et al., 1968Donahue RP Bias WB Renwick JH McKusick VA Probable assignment of the Duffy blood group locus to chromosome 1 in man.Proc Natl Acad Sci USA. 1968; 61: 949-955Crossref PubMed Scopus (179) Google Scholar), making CAE1 the first human disease locus to be assigned to a human autosome. The likelihoods reported by Renwick were estimated by use of a computerized algorithm and were the first to be analyzed in this fashion. In his commentary in 1970, “Eyes on Chromosomes,” Renwick credits the potential for surgical treatment of congenital cataracts, one of the first serious genetic conditions for which effective therapy was available, with stimulating the pioneering work of ophthalmologists such as Nettleship and Usher (Renwick, 1970Renwick JH Eyes on chromosomes.J Med Genet. 1970; 7: 239-243Crossref PubMed Scopus (8) Google Scholar). Congenital cataracts often are dominantly inherited and do not reduce reproductive fitness, so large families suitable for mapping studies are available. However, until recently genetic analysis of cataracts has lagged behind that of retinal degenerations and other ophthalmologic diseases. Following the initial localization of the CAE1 locus, additional genetic studies of congenital cataract demonstrated the challenges arising from genetic heterogeneity, which still confront investigators today. Renwick and Lawler, 1963Renwick JH Lawler SD Probable linkage between a congenital cataract locus and the Duffy blood group locus.Ann Hum Genet. 1963; 27: 67-84Crossref PubMed Scopus (114) Google Scholar reanalyzed data from Mohr on the Marner cataract (CAM), which has a variable phenotype overlapping that of CAE1, and excluded this locus from the Duffy region. In 1973 Hammerstein and Scholtz and in 1978 Huntzinger et al. also excluded from the Duffy region the loci for phenotypically similar cataracts. Conneally et al., 1978Conneally PM Wilson AF Merritt AD Helveston EM Palmer GG Wang LY Confirmation of genetic heterogeneity in autosomal dominant forms of cataracts from linkage studies.Cytogenet Cell Genet. 1978; 22: 295-297Crossref PubMed Scopus (23) Google Scholar confirmed the linkage to the Duffy region in one of seven families studied. With more efficient genetic markers, nine new cataract loci have been described (table 1). Of these, the cataracts in two families map near the Duffy region, the cataracts in three families map to the γ-crystallin cluster at 2q33-q35, and the cataracts in two families map near haptoglobin, at 16q22. The remaining six loci have each been described in a single family. It has been estimated that there are 30 loci responsible for autosomal dominant cataracts in man (Ehling, 1991Ehling UH Genetic risk assessment.Annu Rev Genet. 1991; 25: 255-280Crossref PubMed Scopus (24) Google Scholar). That there are already 22 cataract loci mapped in mice suggests that this might be a low estimate. A gene for recessive cataracts has been localized to the Ii blood-group locus (Ogata et al., 1979Ogata H Okubo Y Akabane T Phenotype i associated with congenital cataract in Japanese.Transfusion. 1979; 19: 166-168Crossref PubMed Scopus (28) Google Scholar), where it is associated with the “I” phenotype in Japanese and some Caucasians, and the Nance-Horan syndrome has been mapped to Xp21-22 (Stambolian et al., 1990Stambolian D Lewis RA Buetow K Bond A Nussbaum R Nance-Horan syndrome: localization within the region Xp21.1-Xp22.3 by linkage analysis.Am J Hum Genet. 1990; 47: 13-19PubMed Google Scholar). Finally, a number of chromosomal abnormalities, genetic syndromes, and metabolic diseases are associated with cataract (Hejtmancik et al., 1995Hejtmancik JF Kaiser-Kupfer MI Piatigorsky J Molecular biology and inherited disorders of the eye lens.in: Scriver CR Beaudet AL Sly WS Valle D The metabolic basis of inherited disease. McGraw Hill, New York1995: 4325-4349Google Scholar).Table 1Mapped Human Cataract LociLocus (Phenotype)MIM NumberChromosomeMorphologyGeneNo. of FamiliesReferenceCAE1 (CZP1, Duffy linked)1162001q21-q25Zonular pulverulentConnexin50 (GJA8)2Renwick and Lawler, 1963Renwick JH Lawler SD Probable linkage between a congenital cataract locus and the Duffy blood group locus.Ann Hum Genet. 1963; 27: 67-84Crossref PubMed Scopus (114) Google ScholarCAM (Marner, CTM)11680016q22Variable (progressive central and zonular nuclear, anterior polar, or stellate)2Eiberg et al., 1988Eiberg H Marner E Rosenberg T Mohr J Marner's cataract (CAM) assigned to chromosome 16: linkage to haptoglobin.Clin Genet. 1988; 34: 272-275Crossref PubMed Scopus (64) Google ScholarCCL (Coppock like)1236602q33q35Nuclear lamellar (Coppock like), aculeiform, variable nuclearγE-crystallin3Lubsen et al., 1987Lubsen NH Renwick JH Tsui LC Breitman ML Schoenmakers JG A locus for a human hereditary cataract is closely linked to the gamma-crystallin gene family.Proc Natl Acad Sci USA. 1987; 84: 489-492Crossref PubMed Scopus (84) Google ScholarCCA1 (cerulean-blue dot)11566017q24Cerulean (nuclear and cortical)1Armitage et al., 1995Armitage MM Kivlin JD Ferrell RE A progressive early onset cataract gene maps to human chromosome 17q24.Nat Genet. 1995; 9: 37-40Crossref PubMed Scopus (82) Google ScholarCCV (Volkmann)1156651p36Variable (progressive central and zonular with sutural component)1Eiberg et al., 1995Eiberg H Lund AM Warburg M Rosenberg T Assignment of congenital cataract Volkmann type (CCV) to chromosome 1p36.Hum Genet. 1995; 96: 33-38Crossref PubMed Scopus (83) Google ScholarCCZS-LSB (zonular sutural)60088117q11-q12Variable nuclear lamellar with sutural componentNear βA3-crystallin1Padma et al., 1995Padma T Ayyagari R Murty JS Basti S Fletcher T Rao GN Kaiser-Kupfer M et al.Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11-12.Am J Hum Genet. 1995; 57: 840-845PubMed Google ScholarCTAA2 (anterior polar)60120217p13Anterior polar1Berry et al., 1996Berry V Ionides AC Moore AT Plant C Bhattacharya SS Shiels A A locus for autosomal dominant anterior polar cataract on chromosome 17p.Hum Mol Genet. 1996; 5: 415-419Crossref PubMed Scopus (64) Google ScholarCCA2 (cerulean-blue dot)60154722qCeruleanβB2-crystallin1Kramer et al., 1996Kramer P Yount J Mitchell T LaMorticella D Carrero-Valenzuela R Louvrien E Maumenee I et al.A second gene for cerulean cataracts maps to the beta crystallin region on chromosome 22.Genomics. 1996; 35: 539-542Crossref PubMed Scopus (52) Google ScholarCZP60188513Zonular pulverulentNear connexin6 (GJA3)1Mackay et al., 1997Mackay D Ionides A Berry V Moore A Bhattacharya S Shiels A A new locus for dominant “zonular pulverulent” cataract, on chromosome 13.Am J Hum Genet. 1997; 60: 1474-1478Abstract Full Text PDF PubMed Scopus (47) Google Scholar Open table in a new tab CCA1 and CCA2, which map to chromosomes 17 and 22, respectively, are both cerulean cataracts, and CAE1, CCL, CAM, and CZP, which map to loci on chromosomes 1, 2, 16, and 13, respectively, are all nuclear or nuclear lamellar (zonular) with some variations—that is, they are sometimes pulverulent or have a sutural or cortical component. This demonstrates the power of linkage studies to distinguish the pathogenesis of a phenotypically similar family of diseases. On the other hand, cataracts within a single family can show remarkable phenotypic variation (Scott et al., 1994Scott MH Hejtmancik JF Wozencraft LA Reuter LM Parks MM Kaiser-Kupfer MI Autosomal dominant congenital cataract: interocular phenotypic heterogeneity.Ophthalmology. 1994; 101: 866-871Abstract Full Text PDF PubMed Scopus (71) Google Scholar). Understanding cataract would be impossible without knowledge of the biology of the lens. In 1894, Morner first described the crystallins as heterogeneous structural proteins found at high concentrations in the lens, and the first crystallin (δ-) was cloned in 1979. The lens crystallins constitute 80%–90% of the soluble protein and, in most species, constitute three main families, called “ubiquitous” crystallins. α-Crystallins can be induced by stress (Klemenz et al., 1991Klemenz R Frohli E Steiger RH Schafer R Aoyama A Alpha B-crystallin is a small heat shock protein.Proc Natl Acad Sci USA. 1991; 88: 3652-3656Crossref PubMed Scopus (472) Google Scholar) and function as molecular chaperones (Horwitz, 1993Horwitz J The function of alpha-crystallin: Proctor lecture.Invest Ophthalmol Vis Sci. 1993; 34: 10-22PubMed Google Scholar). β- and γ-crystallins, which share a common two-domain structure composed of four extremely stable torqued β-pleated sheets termed “Greek key” motifs, are related to the stable spore-coat proteins (Lubsen et al., 1988Lubsen NH Aarts HJM Schoenmakers JGG The evolution of lenticular proteins: the beta- and gamma-crystallin supergene family.Prog Biophys Mol Biol. 1988; 51: 47-76Crossref PubMed Scopus (158) Google Scholar) and to the tumor suppressor A1M1 (Ray et al., 1997Ray ME Wistow G Su YA Meltzer PS Trent JM A1M1, a novel non-lens member of the beta-gamma-crystallin superfamily associated with the control of tumorigenicity in human malignant melanoma.Proc Natl Acad Sci USA. 1997; 7: 3229-3234Crossref Scopus (116) Google Scholar). The α-crystallins are synthesized early in lens development, as the lens vesicle pinches off from the surface ectoderm. Synthesis of the βγ-crystallins increases as anterior epithelial cells move laterally and then into the lens nucleus, elongating and losing their nuclei to form lens fiber cells. The lens crystallins provide cellular cytoplasm consistent with lens transparency, which requires that the refractive index must be relatively constant over distances approximating the wavelength of the transmitted light (Delaye and Tardieu, 1983Delaye M Tardieu A Short-range order of crystallin proteins accounts for eye lens transparency.Nature. 1983; 302: 415-417Crossref PubMed Scopus (619) Google Scholar). This requires maintenance of a high degree of short-range order among the lens crystallins. In addition, because fiber cells in the central lens nucleus lose their nuclei during development, the crystallins in these cells do not turn over. Since most are at least as old as the individual in whose eyes they reside, crystallins must be extremely stable proteins. The classical view of crystallins as lens-specific proteins that allow lens transparency was shaken by the description of taxon-specific, or enzyme, crystallins; these are closely related or identical to enzymes expressed at low concentrations in nonlens tissues, as well as at high concentrations in the lens. Recently some members of the α- and βγ-crystallins were also shown to be expressed outside the lens (Head et al., 1995Head MW Sedowofia K Clayton RM Beta B2-crystallin in the mammalian retina.Exp Eye Res. 1995; 61: 423-428Crossref PubMed Scopus (38) Google Scholar; Kantorow et al., 1997Kantorow M Horwitz J Sergeev YV Hejtmancik JF Piatigorsky J Extralenticular expression cAMP-dependent kinase phosphorylation and autophosphorlyation of betaB2-crystallin.Invest Ophthalmol Vis Sci. 1997; (S205-S205)Google Scholar). Finally, α- and βB2-crystallins have autokinase activity (Kantorow and Piatigorsky, 1994Kantorow M Piatigorsky J Alpha-crystallin/small heat shock protein has autokinase activity.Proc Natl Acad Sci USA. 1994; 91: 3112-3116Crossref PubMed Scopus (123) Google Scholar; Kantorow et al., 1997Kantorow M Horwitz J Sergeev YV Hejtmancik JF Piatigorsky J Extralenticular expression cAMP-dependent kinase phosphorylation and autophosphorlyation of betaB2-crystallin.Invest Ophthalmol Vis Sci. 1997; (S205-S205)Google Scholar), further blurring the distinction between the enzyme crystallins and the ubiquitous crystallins. Lens transparency also requires a variety of noncrystallin proteins. Catalase, the glutathione redox cycle, and the mercaptopuric pathway are critical for maintenance of a reducing environment in the lens (Spector, 1995Spector A Oxidative stress-induced cataract: mechanism of action.FASEB J. 1995; 9: 1173-1182Crossref PubMed Scopus (753) Google Scholar). The lens cytoskeleton supports cellular architecture, especially the beaded filament, which appears to be unique to the lens and which may interact with α-crystallin (Carter et al., 1995Carter JM Hutcheson AM Quinlan RA In vitro studies on the assembly properties of the lens proteins CP49, CP115: coassembly with alpha-crystallin but not with vimentin.Exp Eye Res. 1995; 60: 181-192Crossref PubMed Scopus (102) Google Scholar). Membrane proteins such as MP-26 and aquaporins in thin junctions and the connexins and N-cadherin in gap junctions provide osmoregulation and help to maintain the intracellular environment (Gruijters et al., 1987Gruijters WT Kistler J Bullivant S Goodenough DA Immunolocalization of MP70 in lens fiber 16–17-nm intercellular junctions.J Cell Biol. 1987; 104: 565-572Crossref PubMed Scopus (78) Google Scholar). Finally, developmental regulation by factors such as Pax-6 is critical for formation of the lens architecture (Cvekl and Piatigorsky, 1996Cvekl A Piatigorsky J Lens development and crystallin gene expression: many roles for Pax-6.BioEssays. 1996; 18: 621-630Crossref PubMed Scopus (241) Google Scholar). Each component of these systems would be a candidate for causing hereditary cataract. Initial insights into the genetic causes of cataract came from animal models, mostly mice. Of the mutations associated with animal models of cataract, four are in crystallin genes, and four more are in membrane proteins—three in MP-26 and one in MP-19 (table 2). The mutations characterized so far confirm the importance of membrane proteins, which modulate exchange of ions and metabolites between lens fibers, epithelial cells, and the extracellular space. The existence of a second group of mutations reemphasizes the importance of the lens crystallins in the maintenance of lens transparency. All the crystallin mutations characterized to date are predicted to disrupt the tertiary structure of the given crystallin, precipitating from solution with it any associated crystallins. In addition, there are a number of genetically engineered mouse models with cataract resulting either from abnormalities of development (Lang et al., 1987Lang RA Metcalf D Cuthbertson RA Lyons I Stanley E Kelso A Kannourakis G et al.Transgenic mice expressing a hemopoetic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage.Cell. 1987; 51: 675-686Abstract Full Text PDF PubMed Scopus (281) Google Scholar; Perez-Castro et al., 1993Perez-Castro AV Tran VT Nguyen-Huu MC Defective lens fiber differentiation and pancreatic tumorigenesis caused by ectopic expression of the cellular retinoic acid-binding protein I.Development. 1993; 119: 363-375PubMed Google Scholar), immunity (Egwuagu et al., 1994Egwuagu CE Sztein J Chan CC Reid W Mahdi R Nussenblatt RB Chepelinsky AB Ectopic expression of gamma interferon in the eyes of transgenic mice induces ocular pathology and MHC class II gene expression.Invest Ophthalmol Vis Sci. 1994; 35: 332-341PubMed Google Scholar; Geiger et al., 1994Geiger K Howes E Gallina M Huang XJ Travis GH Sarvetnick N Transgenic mice expressing IFN-gamma in the retina develop inflammation of the eye and photoreceptor loss.Invest Ophthalmol Vis Sci. 1994; 35: 2667-2681PubMed Google Scholar), growth (Mahon et al., 1987Mahon KA Chepelinsky AB Khillan JS Overbeek PA Piatigorsky J Westphal H Oncogenesis of the lens in transgenic mice.Science. 1987; 235: 1622-1628Crossref PubMed Scopus (130) Google Scholar; Eva et al., 1991Eva A Graziani G Zannini M Merin LM Khillan JS Overbeek PA Dominant dysplasia of the lens in transgenic mice expressing the dbl oncogene.New Biol. 1991; 3: 158-168PubMed Google Scholar; Griep et al., 1993Griep AE Herber R Jeon S Lohse JK Dubielzig RR Lambert PF Tumorigenicity by human papillomavirus type 16 E6 and E7 in transgenic mice correlates with alterations in epithelial cell growth and differentiation.J Virol. 1993; 67: 1373-1384PubMed Google Scholar), cytoskeleton (Capetanaki et al., 1989Capetanaki Y Smith S Heath JP Overexpression of the vimentin gene in transgenic mice inhibits normal lens cell differentiation.J Cell Biol. 1989; 109: 1653-1664Crossref PubMed Scopus (115) Google Scholar; Bloemendal et al., 1997Bloemendal H Raats JM Pieper FR Benedetti EL Dunia I Transgenic mice carrying chimeric or mutated type III intermediate filament (IF) genes.Cell Mol Life Sci. 1997; 53: 1-12Crossref PubMed Scopus (10) Google Scholar), membrane transport (Dunia et al., 1996Dunia I Smit JJ van der Valk MA Bloemendal H Borst P Benedetti EL Human multidrug resistance 3-P-glycoprotein expression in transgenic mice induces lens membrane alterations leading to cataract.J Cell Biol. 1996; 132: 701-716Crossref PubMed Scopus (16) Google Scholar), or lens crystallins (Brady et al., 1997Brady JP Garland D Duglas-Tabor Y Robison Jr, WG Groome A Wawrousek EF Targeted disruption of the mouse alpha A-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein alpha B-crystallin.Proc Natl Acad Sci USA. 1997; 94: 884-889Crossref PubMed Scopus (285) Google Scholar) or from proteolysis of lens proteins (Mitton et al., 1996Mitton KP Kamiya T Tumminia SJ Russell P Cysteine protease activated by expression of HIV-1 protease in transgenic mice. MIP26 (aquaporin-0) cleavage and cataract formation in vivo and ex vivo.J Biol Chem. 1996; 271: 31803-31806Crossref PubMed Scopus (12) Google Scholar). Although some of these results are difficult to interpret precisely, they do suggest cellular systems that might be involved in hereditary human cataract, generally consistent with but extending other studies of animal and human cataracts.Table 2Animal Models of CataractModelProteinMutationMechanismReferencePhilly mouseβB2-crystallin12-bp In-frame deletionDisrupts tertiary structureChambers and Russell, 1991Chambers C Russell P Deletion mutation in an eye lens beta-crystallin: an animal model for inherited cataract.J Biol Chem. 1991; 266: 6742-6746Abstract Full Text PDF PubMed Google ScholarELO mouseγE-crystallinFrameshiftFrameshiftCartier et al., 1992Cartier M Breitman ML Tsui LC A frameshift mutation in the gammaE-crystallin gene of the ELO mouse.Nat Genet. 1992; 2: 42-45Crossref PubMed Scopus (82) Google Scholar13/N guinea pigζ-CrystallinSplice error6-Amino-acid deletion from skipped exonRodriguez et al., 1992Rodriguez IR Gonzalez P Zigler Jr, JS Borras T A guineq-pig hereditary cataract contains a splice-site deletion in a crystallin gene.Biochim Biophys Acta. 1992; 1180: 44-52Crossref PubMed Scopus (53) Google ScholarCat3 mouseγ-CrystallinUnknownDecreased γ-crystallin mRNASanthiya et al., 1995Santhiya ST Abd-alla SM Loster J Graw J Reduced levels of gamma-crystallin transcripts during embryonic development of murine Cat2nop mutant lenses.Graefes Arch Clin Exp Ophthalmol. 1995; 233: 795-800Crossref PubMed Scopus (21) Google ScholarFraser mouseMP-26Splice errorCarboxy terminus replaced by long terminal repeat sequenceShiels and Bassnett, 1996Shiels A Bassnett S Mutations in the founder of the MIP gene family underlie cataract development in the mouse.Nat Genet. 1996; 12: 212-215Crossref PubMed Scopus (209) Google ScholarLOP mouseMP-26A55PDisrupts targeting to membraneShiels and Bassnett, 1996Shiels A Bassnett S Mutations in the founder of the MIP gene family underlie cataract development in the mouse.Nat Genet. 1996; 12: 212-215Crossref PubMed Scopus (209) Google ScholarTo3 mouseMP-19 (myelin precursor)G15VDisrupts first α-helical transmembraneSteele et al., 1997Steele EC Kerscher S Lyon MF Glenister PH Favor J Wang JH Church RL et al.Identification of a mutation in the MP19 gene, Lim2, in the cataractous mouse mutant To3..Mol Vis. 1997; 3: 5(http://www.emory.edu/molvis/v3/steele)PubMed Google ScholarHf1 mouseMP-2676-bp In-frame deletionIn-frame deletion of exon 2 (55 amino acids)Chepelinsky et al., 1997Chepelinsky AB Sidjanin DJ Parker-Wilson DM Exon 2 deletion in the transcript encoding the lens major intrinsic protein (MIP) results in a mouse genetic cataract.Invest Ophthalmol Vis Sci. 1997; (S934-S934)Google Scholar Open table in a new tab To date, mutations in three genes have been associated with human autosomal dominant cataract. In humans, the γE-crystallin gene is a pseudogene, having an inactive promoter and a termination mutation in the second exon (which would form the first globular domain of the protein). In the Coppock-like cataract, base changes in the promoter of the ιγE-crystallin gene increase expression of the truncated product 10-fold, to ∼30% of the level of γD-crystallin, the first human disease associated with reactivation of a pseudogene (Brakenhoff et al., 1994Brakenhoff RH Henskens HAM van Rossum MWPC Lubsen NH Schoenmakers JGG Activation of the gammaE-crystallin pseudogene in the human hereditary Coppock-like cataract.Hum Mol Genet. 1994; 3: 279-283Crossref PubMed Scopus (86) Google Scholar). Similarly, in the autosomal dominant cerulean cataract localized to chromosome 22, βB2-crystallin is truncated because of a nonsense mutation at the beginning of exon 6, which encodes the fourth Greek key motif (Litt et al., 1997Litt M Carrero-Valenzuela R LaMorticella DM Schultz DW Mitchell TN Kramer P Maumenee IH Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human beta-crystallin gene CRYBB2.Hum Mol Genet. 1997; 6: 665-668Crossref PubMed Scopus (220) Google Scholar). Presumably, both these gene products fold improperly, disturbing the supramolecular organization of the remaining crystallins and eventually becoming unstable in solution, leading to opacity. Now, in this issue of the Journal, Shiels et al. provide a convincing rationale for a cataract occurring as a result of aberrant intercellular transport of small molecules, because of mutation of a highly conserved proline in the gap-junction protein connexin50. Since a large part of the metabolic activity of the lens resides in the anterior epithelium, with the resulting requirement that metabolites be transferred to the nuclear fiber cells, the lens would be particularly susceptible to such a lesion. Because human lens material is not always easily obtainable, final confirmation of these mutations as causative may have to await transgenic expression of the mutant molecules. However, Gong et al., 1997Gong X Li E Klier G Huang Q Wu Y Lei H Kuman NM et al.Disruption of alpha3–connexin gene leads to proteolysis and cataractogenesis in mice.Cell. 1997; 91: 833-843Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar have recently shown that disruption of connexin46, which associates in the same gap-junction plaques with connexin50, causes cataract in mice, providing strong support for a causative role of connexin50 in the CAE1 cataract. In general, cataracts can be envisioned as falling into two groups. One group involves disruption of lens development and uncontrolled cell division, leading to the loss of cellular order in the lens and to light scattering. A second group results from aberrations of the lens crystallins or the intracellular environment, disrupting the ability of the crystallins to interact in a close and orderly fashion and causing them to aggregate or to precipitate and scatter light. These two processes are not necessarily mutually exclusive. Anterior epithelial cells that fail to differentiate into lens fibers are unlikely to synthesize appropriate concentrations of crystallins. Furthermore, there is suggestive evidence that at least some crystallins may be necessary for normal fiber-cell differentiation (Graw, 1996Graw J Cataract mutations as a tool for developmental geneticists.Ophthalmic Res. 1996; 28: 8-18Crossref PubMed Scopus (13) Google Scholar). Finally, osmotically induced cataracts (e.g., sugar cataracts) lead not only to abnormalities of the crystallins but also to formation of blebs and vacuoles that would disrupt the optical properties of the lens, in a fashion similar to cellular disarray. Although congenital cataracts are relatively easy to study, most visual morbidity in Western populations comes from age-related cataract. We would like to be able to extrapolate our experience with congenital cataracts to age-related cataracts. Currently, the only firm information on the causes of age-related cataract comes from epidemiological studies implicating exposure to UV light (Rosmini et al., 1994Rosmini F Stazi MA Milton RC Sperduto RD Pasquini P Maraini G A dose-response effect between a sunlight index and age-related cataracts: Italian-American Cataract Study Group.Ann Epidemiol. 1994; 4: 266-270Abstract Full Text PDF PubMed Scopus (30) Google Scholar) and exposure to cigarette or wood smoke (during cooking) (Shalini et al., 1994Shalini VK Luthra M Srinivas L Rao SH Basti S Reddy M Balasubramian D et al.Oxidative damage to the eye lens caused by cigarette smoke and fuel smoke condensates.Indian J Biochem Biophys. 1994; 31: 261-266PubMed Google Scholar). Although there are some tantalizing data suggesting that autoimmunity (Singh et al., 1995Singh DP Guru SC Kikuchi T Abe T Shinohara T Autoantibodies against beta-crystallins induce lens epithelial cell damage and cataract formation in mice.J Immunol. 1995; 155: 993-999PubMed Google Scholar) or abnormal cell division (Liu et al., 1994Liu J Hales AM Chamberlain CG McAvoy JW Induction of cataract-like changes in rat lens epithelial explants by transforming growth factor beta.Invest Ophthalmol Vis Sci. 1994; 35: 388-401PubMed Google Scholar) contributes to age-related cataract, oxidative damage is currently held to be the most common cause of age-related cataract. Simplistically stated, a variety of environmental insults, including exposure to UV light, osmotic perturbation, and direct oxidative stress, have been shown to threaten the reducing environment normally maintained in the lens (Spector, 1995Spector A Oxidative stress-induced cataract: mechanism of action.FASEB J. 1995; 9: 1173-1182Crossref PubMed Scopus (753) Google Scholar). In addition to damaging membranes and DNA, with time the cumulative damage resulting from oxidative stress destabilizes the lens crystallins, which partially denature. These are initially bound by α-crystallin, which serves as a chaperone, to protect the lens cells from damaged proteins. However, α-crystallin cannot renature proteins and release them in the fashion of a true chaperone but, rather, holds them in large soluble aggregates. In time the “buffer capacity” of α-crystallin is overcome, and large masses of insoluble crystallins precipitate from solution, leading to opacity. Candidate genes that contribute to age-related cataract include not only those capable of causing congenital cataracts but also genes encoding enzymes that protect the lens from oxidation or other types of environmental insults. Dissecting the mechanisms of age-related cataract promises to be challenging, and identifying the specific genes involved may depend on completion of an expressed sequence map of the human genome, to provide candidate genes in risk regions. Although this task seems daunting, it is no greater than that faced by geneticists 2 or 3 decades ago as they began to map Mendelian traits. In 1970 Renwick estimated that “samples from 200 suitable individuals for 20 markers would probably be adequate for picking up about 50% of the markers ‘close enough’ to the disease locus” (Renwick, 1970Renwick JH Eyes on chromosomes.J Med Genet. 1970; 7: 239-243Crossref PubMed Scopus (8) Google Scholar, p. 239), giving an overall success rate of ∼1/4. A knowledge of the genetic contribution to age-related cataract will allow more-accurate epidemiological studies, targeted at genetic subpopulations with increased risk for the specific environmental factor under study. Together, a combination of clinical-epidemiological and genetic studies will allow both presymptomatic prediction of risk for development of age-related cataract and rational design and application of measures to prevent or delay the onset of age-related cataract. I would like to thank Drs. Joe Horwitz, Muriel Kaiser-Kupfer, Mark Kantorow, Eric Wawrousek, and Sam Zigler for a close reading of the manuscript.