Am. J. Hum. Genet. 57:840-845, 1995

Autosomal Dominant Zonular Cataract with Sutural OpacitiesLocalized to Chromosome 1 7q I 1- 12

T. Padma,"2 R. Ayyagari,' J. S. Murty,2 S. Basti,3 T. Fletcher,' G. N. Rao,' M. Kaiser-Kupfer,and J. F. Hejtmancik'

'National Eye Institute, Bethesda; and 2Department of Genetics, Osmania University, and 3L V. Prasad Eye Institute, Hyderabad

Summary

Congenital cataracts constitute a morphologically andgenetically heterogeneous group of diseases that are amajor cause of childhood blindness. Different loci forhereditary congenital cataracts have been mapped tochromosomes 1, 2, 16, and 17q24. We report linkageof a gene causing a unique form of autosomal dominantzonular cataracts with Y-sutural opacities to chromo-some 17q11-12 in a three-generation family exhibitinga maximum lod score of 3.9 at D17S805. Multipointanalysis gave a 1-lod confidence interval of 17 cM. Thisinterval is bounded by the markers D17S799 andD1 7S798, a region that would encompass a number ofcandidate genes including that coding for PA3/A1-crys-tallin.

Introduction

Congenital cataracts are a significant cause of visualdisease, being responsible for approximately one-thirdof blindness in infants. Without prompt treatment, cata-racts may interfere with sharp imaging on the retina,resulting in failure to develop normal visual cortical syn-aptic connections and placing children at risk for irre-versible visual loss. Congenital cataracts form a hetero-geneous group of diseases, both genetic and en-vironmental. When genetic, they can be inherited in anautosomal dominant, recessive, or X-linked fashion(Hejtmancik et al. 1995). However, most familial con-genital and childhood cataracts are autosomal dominant(Robb 1994). Dominantly inherited cataracts are them-selves genetically heterogeneous. Clinically identical cat-aracts can map to different loci (Conneally et al. 1978).In addition, inherited cataracts can show intrafamilialphenotypic variability (Scott et al. 1994), indicating thateven identical mutations in the same gene can producea different phenotype, depending on the environmental

Received October 12, 1995; accepted for publication July 18, 1995.Address for correspondence and reprints: Dr. J. Fielding Hejtman-

cik, LMOD/NEI/NIH, Building 6, Room 2A14, Bethesda, MD 20892-1996. E-mail f3h@helix.nih.gove 1995 by The American Society of Human Genetics. All rights reserved.0002-9297/9S/5704-0014$02.00

and genetic background. This has complicated effortsto determine the inheritance patterns and to performgene mapping of inherited cataracts.

Zonular cataracts, which show opacification of a dis-crete layer of fiber cells, are the most common type ofhereditary congenital cataracts. Fibers internal and ex-ternal to the opacity remain clear. The position andthickness of the opacity provide clues to the timing ofthe insult causing the cataract. There are also variationsin the degree of opacification, with cataracts rangingfrom dense uniform opaque regions to a dotted ordusted appearance. Zonular cataracts that have beendescribed and mapped include the CAE cataract mappednear Duffy on chromosome lq (Renwick and Lawler1963), the Coppock-like cataract associated with a mu-tation in the WryE-crystallin promoter on chromosome2q (Lubsen et al. 1987; Brakenhoff et al. 1994), and theMarner cataract linked to haptoglobin on chromosome16q (Eiberg et al. 1988; Marner et al. 1989). A ceruleancataract maps to chromosome 17q24 (Armitage et al.1995).

Sutural cataracts can show either a dominant or anX-linked inheritance pattern. They show opacificationof the juxtaposed ends of the secondary lens fiber cells,usually having a Y-like shape. An X-linked form of totalnuclear cataract has been described in which female car-riers have posterior sutural opacities (Fraccaro et al.1967), and certain of the patients in the family describedby Marner had sutural opacities (Marner et al. 1989).However, in general, sutural cataracts are distinct fromand are not associated with other forms of hereditarycataract.We have described a three-generation family with iso-

lated autosomal dominant cataracts in which both zonu-lar and sutural opacities coexist (Basti et al., in press;see pedigree in fig. 1). There is intrafamilial phenotypicheterogeneity. Opacities vary from a uniform denseopacity to a collection of fine dots forming a hazy cloud.Initial mapping efforts excluded linkage to regions towhich other zonular cataracts (Duffy, haptoglobin, andy-crystallin) had been mapped. Here, we describe linkageof this zonular congenital cataract with sutural opacitiesto markers on chromosome 17q near the PA3/A1-crys-tallin gene.

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2272312

9 10 11 14 16 17 20 212 2 2 2 2 3 1 1 1 2 1 1 3 1 3 221 E1 2 1 1 3 1 2 1 _X1 3 1235 315 7 2 1 4 5 5 2 4 231 1 2 1 2 2 2 2 2 2 22 4 24 3 4 2 4 3 2 32 1 4 1 4 X4 1 4 1 1 1 1 4 3 4 3 4 1 1 1 13 6 3 1 2 6 3 3 7 3 7 3 2 2 2 2

Figure I Pedigree of the family used for linkage and describedby Basti et al. (in press), including family members used in linkageanalysis and those necessary to show their relationships. Affected indi-viduals are shaded black. Markers, from top (centromeric) to bottom(telomeric), are D17S799*, D17S71, D17S805*, NFl, D17S798*,D17S800*, and D17S250. Markers included in the Genfthon mapand used in multipoint mapping are indicated by an asterisk. Haplo-type phasing was determined to minimize recombination. Markerswith alleles conserved in all disease-bearing individuals are boxed.Obligate recombination events are indicated by an "x." The recombi-nation event in individual 21 could not be unambiguously placed distalto NF1, but it is shown between NFl and D17S798, on the basis ofthe likelihood of allele 3 being maternally inherited. Consanguineousmatings occurred between individuals 12 (unaffected son of an unaf-fected sister of individual 3) and 13 and between individuals 18 (unaf-fected son of an unaffected sister of individual 3) and 19.

Patients and Methods

Pedigrees and DiagnosisThe proband was a 17-year-old male presenting with

bilateral congenital cataracts. He had a positive familyhistory for cataracts (fig. 1). The proband and his familymembers were examined (by S.B.) at the L. V. PrasadEye Institute in Hyderabad. Patient studies and informedconsent were approved by the L. V. Prasad InstitutionalReview Board, the National Eye Institute InstitutionalReview Board, and the National Institutes of HealthOffice of Protection from Research Risks. Detailed ocu-lar, medical, and family histories were obtained fromeach available family member. Clinical and ophthalmo-logical examination included a dilated slit-lamp exami-nation with photographs of significant findings, Snellenvisual acuity testing, intraocular-pressure measurementby applanation tonometry, and fundus examination. Allaffected family members showed a zonular cataract thatmeasured 3.5-4 mm in diameter, an erect Y-shaped an-terior sutural cataract (fig. 2A), and an inverted Y-shaped posterior sutural cataract. The fetal and embry-

onic nuclei within the zonular cataract were clear (fig.2B) except for a few dotlike white opacities. The degreeof opacification of the zonular cataract showed somevariability among affected family members, with threeindividuals (4, 16, and 17 in fig. 1) showing zonularcataracts that were significantly less dense than those inthe remaining family members. A detailed descriptionof the clinical features of all affected individuals is avail-able in the report by Basti et al. (in press).

Genotype AnalysesDNA was isolated either from blood directly or from

transformed lymphoblastoid lines, as described else-where (Smith et al. 1992). PCR and electrophoresis wereperformed as described elsewhere (Smith et al. 1992).Reaction conditions were modified slightly to optimizeamplification and detection. Prior to PCR reactions, 1.5nmol of a single primer of each pair was end-labeled

Figure 2 Slit-lamp photographs of the right eye of individual10, showing well-defined zonular (A, thicker arrow) and anterior su-tural (A and B., thinner arrow) cataracts. The area enclosed by thezonular cataract is clear except for a few dotlike opacities. (Reprintedfrom Basti et al. [in press], with permission from The American Journalof Ophthalmology)

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Table I

Two-Point Lod Scores for Chromosome 17 Markers near the DA3/AI -Crystallin Gene

LOD SCORE AT 0 =

Locus .00 .01 .05 .10 .20 .30 .40 Zmax Omax

D1 7S799 ......... -00 -.72 -.08 .13 .26 .25 .15 .27 .23D1 7S71 .......... 1.50 1.48 1.39 1.27 1.02 .73 .39 1.50 .00D1 7S805 ......... 3.91 3.85 3.60 3.27 2.55 1.74 .84 3.91 .00NF1 .......... 3.85 3.79 3.54 3.22 2.51 1.71 .82 3.85 .00D1 7S798 ......... -00 1.76 2.23 2.23 1.88 1.32 .63 2.27 .07D1 7S800 ......... -00 -1.02 .20 .59 .74 .58 .29 .75 .18D1 7S250 ......... -00 -.51 .11 .32 .41 .36 .21 .42 .21

with 32PATP by incubation, for 30 min at 370C with 5units of T4 kinase, and 50 pmol of primer was addeddirectly to the PCR reaction without further cleaning.The reaction mix was supplemented with unlabeled oli-gonucleotides (50 pmol corresponding to the labeledprimer and 100 pmol for the other of the pair). Primersand amplification conditions were taken from the Ge-nome Database at the Welch Library at Johns HopkinsUniversity. All autoradiograms were independently readby three individuals, without reference to affectationstatus or pedigree, with any disagreement resulting ini-tially in reevaluation of that autoradiogram. If that didnot resolve the interpretation, the marker was testedagain. Family relationships were confirmed by observa-tion of Mendelian inheritance of a total of 34 microsatel-lite markers.

Linkage AnalysisThe LINKAGE program package, version 5.1, was

used for linkage analysis (Lathrop and Lalouel 1984),with MLINK and ILINK used for two-point analysis andwith LINKMAP used for multipoint analysis. Resultsof the multipoint analysis, performed to more closelylocalize the cataract locus among the STS markers inthe region, are reported as multipoint lod scores (loca-tion scores divided by 4.6). Any individual having cata-racts with the appropriate lamellar morphology accom-panied by sutural opacities was considered affected.Individual 2 also had a superimposed senile cataract (seeBasti et al. 1993). Examination of the pedigree suggesteda high penetrance, with 9 of 14 offspring of affectedindividuals being affected. However, because of thesmall family size, estimates of penetrance are tenuous.Thus, all two-point analyses were carried out with pene-trances, for one or two affected alleles and no affectedalleles, of 1.0 and 0, .9 and .1, .5 and 0, as well asby using affected individuals only, with critical valuesdescribed in Results. Results presented in table 1 andfigure 2 were obtained with full penetrance and no phe-nocopies. Similarly, all two-point analyses were carried

out with both Of/0m = 1 and Of 0m = 1.46, recommendedby the CEPH/NIH consortium, with critical values de-scribed in Results. The two-point data were analyzedboth with and without the consanguineous matings be-tween individuals 12 and 13 and between 18 and 19(fig. 1), with no significant difference, and the multipointanalysis was performed without including the consan-guineous matings.A gene frequency of .001 was assumed for the cataract

allele, although varying this value also had only smalleffect on the results. Marker allele frequencies were esti-mated by analyzing 90-100 chromosomes from unre-lated individuals from the Hindu population of India,predominantly from the state of Andrah Pradesh. Thereference population was not controlled for caste. How-ever, two recent studies (Bamshad et al. 1995; Mountainet al. 1995) disclosed no clear separation of allelesamong castes, although both of these studies usedmtDNA sequences. No statistically significant associa-tion between alleles at any two markers was detected inthis population, although the power of this analysis wasweakened by the large number of alleles for eachmarker. Markers in figure 1 are shown in an orderaccording to (1) the CEPH/NIH (D17S250 and NF1;NIH/CEPH Collaborative Mapping Group 1992), theCHLC (D17S71 and D17S798; Buetow et al. 1994),and Genethon (D1 7S799, D1 7S805, D1 7S798, andD1 7S800; Gyapay et al. 1994) maps and (2) our data,including analysis of the cataract family and all markersshown in CEPH pedigrees and using the build procedureof CRIMAP and extracting data from the public CHLCdatabase (ftp.chlc.org) (Lander and Green 1987). Mark-ers D1 7S250, NF1, and Dl 7S71 could not be unambig-uously placed (with respect to markers D1 7S800,Dl 7S805, and Dl 7S805, respectively) with odds> 1,000:1. Thus multipoint analysis was performed withmarkers included in the Genethon map only (Gyapayet al. 1994), by performing three-point analyses of thecataract locus across adjacent markers and deriving acomposite lod-score curve from these (Terwilliger and

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Padma et al.: Cataracts Map to 17q

Ott 1994). Conversion from recombination fraction (0)to genetic distance was according to the method of Ko-sambi (1944). Before multipoint analyses were per-formed, the results were recoded to a maximum of fouralleles by using the Cyrillic pedigree editor utility (C. J.Chapman, Cherwell Scientific, Oxford) and were con-

firmed by hand, both methods using the data-reductionmethod of Ott (1978). Recoding produced no changesin the two-point results.

Results

After exclusion of regions known to contain cataractloci, including Duffy, the y-crystallin gene cluster, andhaptoglobin (Basti et al., in press), other genes were

considered as candidates, on the basis of both their highlevels of expression in the lens and known function inmaintaining lens transparency. Linkage was excludedfrom markers flanking glutathione reductase, aA-crys-tallin, and the linked 1B2- and OB3-crystallin genes (datanot shown). However, two markers near the jA3/A1-crystallin gene on chromosome 17q gave results sugges-

tive of linkage, although a lod score of 3 was notreached: D1 7S798, maxium lod score (Zmax) = 2.27 atmaximum 0 (Omax) = .07; and D17S800, Zmax = 0.75at Omax = .18.

Seven microsatellite markers located near the regionof interest were selected by their location by use of theNIHICEPH collaborative map (NIHICEPH Collabora-tive Mapping Group 1992), the CHLC map (Buetow etal. 1994), and the 1993-94 linkage map by Genethon(Gyapay et al. 1994). The genotyping results for familymembers are shown in figure 1, and two-point linkageresults of these markers are shown in table 1. Themarker order in the figure and table is consistent withthe best estimate of chromosomal order (see Methods).Markers D1 7S71, Dl 7S805, and NF1 showed no obli-gate recombination, whereas D1 7S799 (centromeric),D1 7S798 (telomeric), and D1 7S800 (telomeric) showobligate recombinations, with Zmax values at 0 = .23,.07, and .18, respectively. Zmax values >3 resulted fromanalysis with markers D17S805 (Zmax = 3.91 at Omax

= 0) and NF1 (Zmax = 3.85 at Omax = 0).Because of difficulties in estimating the penetrance of

the cataract gene in a single family, the effect that vary-

ing the penetrance had on the lod scores obtained withthese two markers was determined. Zmax for bothD1 7S805 and NF1 was >3.3 for combinations of pene-trance values >.9 and false-positive (phenocopy) values<.1. The maximum values (3.91 for D1 7S805 and 3.85for NF1) occurred with full penetrance and no false-positive diagnoses. Significant lod scores (Zmax > 3.0)occurred with penetrances >.5, if no phenocopies were

assumed. When only affected individuals were analyzed,the lod score obtained with D1 7S805 was 1.75, and

that with NF1 was 1.10, both with no recombinations(0 = 0). As expected for these nonrecombinant markers,varying Of/0m from 1 to 1.46, the value recommended forthis region by the NIH/CEPH Collaborative MappingGroup (NIH/CEPH Collaborative Mapping Group1992), resulted in no change in Zmax.Multipoint analysis of cataracts in this family, by use

of intermarker distances from the 1993-94 linkage mapderived by Genethon (Gyapay et al. 1994), gave amultipoint Zmax of 3.91 at D1 7S805, with a 1-lod con-fidence interval extending over 17 cM, from 5 cMtelomeric of D17S799 to D17S798. The Zmax obtainedwith multipoint analysis is the same as that obtainedwith D1 7S805 alone, which is expected, since D1 7S805is fully informative. Examination of the haplotype dataplaced the cataract locus between markers D1 7S799 andD17S798, a localization similar to that seen with thetwo-point and multipoint mapping (fig. 1). No obligaterecombinations were seen between the cataracts andmarkers D17S71, D17S805, and NF1. The candidateregion was delimited proximally by a single recombina-tion event with D17S799 in individual 17, an affectedmale. Similarly, distal obligate recombinants were notedwith D1 7S800 in individual 5, an unaffected male, andwith D1 7S798 in individual 21, an affected female. Al-though the recombination event in individual 21 couldhave occurred proximal to NFl, the probable inheri-tance of individual 21's allele 3 of NFl from her mothersuggests that the recombination event occurred betweenNFl and D1 7S798 (see Discussion).

Discussion

These results localize a fifth gene for autosomal domi-nant congenital cataracts to chromosome 17, betweenD17S799 and D17S798. Although four of the mappedcataracts can be classified morphologically as lamellaror zonular, each has phenotypically distinguishing char-acteristics. The cataracts in this family are unique inhaving uniformly associated sutural opacities. Althoughit is difficult to estimate precisely what the occurrenceof this morphological type of cataract among nonheredi-tary congenital cataracts might be, it seems likely, fromour experience, that they would be rare. In this case,this cataract locus would be more firmly placed betweenthe delimiting markers D1 7S799 and D1 7S798.

Because of the complexity of the population of theIndian subcontinent, there are some difficulties in de-termining the appropriate marker allele frequencies touse (see Methods). The alleles of most individuals in thefamily are known directly or can be inferred, so that thelod scores should be relatively stable to changes in allelefrequencies. For example, the alleles of D1 7S805 areknown for all family members, so that the lod scoreobtained with this marker is independent of marker al-

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844 Am. J. Hum. Genet. 57:840-845, 1995

lele frequencies. The affect of allele frequencies can besignificant, however. This is best seen by comparing thelod scores of D17S805 and NF1. For NF1, individuals16, 17, and 21 could have inherited either allele 2 orallele 3 from their fathers, who were not available forstudy. The small difference between the lod scores ob-tained with these markers (3.91 with Dl 7S805 and 3.85with NF1, both at 0 = 0) is a result of (a) the lowfrequency of allele 3 (.07), relative to that of allele 2(.49), in the Indian population and (b) the obligate oc-currence on allele 2 in the fathers (individuals 12 and18), because they have children homozygous for allele2 (individuals 14 and 20, respectively).

Using currently available markers, linkage analysis lo-calizes the cataract gene in this family to a 17-cM regionof proximal chromosome 17q. The qll.1-q12 region ofchromosome 17 contains a number of potential candi-date genes, including PA1/A3- crystallin, neurofibromin1, thyroid hormone receptor a, and pancreatic polypep-tide. Homeobox B6, located slightly telomeric at 17q21-q22, might also be considered. However, one of thestrongest candidate genes in this area is PA1/A3-crys-tallin, located at 17q11.2-q12.The ,BA1/A3-crystallin gene has a number of proper-

ties that make it a reasonable candidate gene. As a lenscrystallin, it is a structural protein expressed at highlevels and contributing to lens transparency (Delaye andTardieu 1983). In both chick and rat embryos, the JiA3-crystallin has been shown to be expressed in the earlysecondary lens fibers (Hejtmancik et al. 1985; Aarts etal. 1989), consistent with the pattern of opacificationin this cataract. Although it is unclear why a mutantcrystallin would not also cause opacification of fibersappearing later in lens development, activation of thehuman pyE-crystallin gene is felt to be responsible forautosomal dominant zonular cataracts in a Dutch family(Brakenhoff et al. 1994). The ELO cataract in mice re-sults from a frameshift mutation in the yE-crystallin gene(Cartier et al. 1992). A 12-bp deletion in the PB2-crys-tallin gene is responsible for autosomal codominant cat-aracts in the Philly mouse (Chambers and Russell 1991).Finally, truncation of the amino-terminal arm of themouse 13A3-crystallin has been shown to decrease itsassociation into macromolecular aggregates (Hope et al.1994), felt to be important for lens transparency. Thus,there is ample precedent for aberrant crystallins-and,By-crystallins, in particular-causing cataracts.

In summary, we present evidence for a new locus forautosomal dominant congenital cataracts, bringing thetotal of loci mapped by linkage analysis to five. Twomore loci have been localized by coinheritance with bal-anced chromosomal translocations. These loci almostcertainly represent a small minority of the genetic causesof cataracts, since, to date, most loci have been identifiedin only one family studied. Currently this new cataract

locus is being further characterized by fine mapping andanalysis of candidate genes in the region.

AcknowledgmentsWe thank Ms. L. Lee for expert technical assistance with

cell transformation and culture, and we thank Drs. MihaelisPolymeropoulos, Dan Jones, and Steven L. Bernstein for adviceand constructive criticism of the manuscript.

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