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(Investigative Ophthalmology and Visual Science. 2005;46:623-626.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-0955
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A New Locus for Autosomal Recessive Nuclear Cataract Mapped to Chromosome 19q13 in a Pakistani Family

S. Amer Riazuddin,1,2,3 Afshan Yasmeen,2,3 Qingjiong Zhang,1 Wenliang Yao,1 Muhammad Farooq Sabar,2 Zahoor Ahmed,2 Sheikh Riazuddin,2,3 and J. Fielding Hejtmancik1,3

1From the Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland; and the 2National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To identify the disease locus of autosomal recessive congenital nuclear cataracts in a consanguineous Pakistani family.

METHODS. A large Pakistani family with multiple individuals affected by autosomal recessive congenital cataracts was ascertained. Patients were examined, blood samples were collected, and DNA was isolated. A genome-wide scan was performed using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members. Two-point lod scores were calculated, and haplotypes were formed by inspection.

RESULTS. In the genome-wide scan, a maximum lod score of 2.89 was obtained for marker D19S414 on 19q13. Fine mapping using D19S931, D19S433, D19S928, D19S225, D19S416, D19S213, D19S425, and D19S220 markers from the Généthon database showed that markers in a 14.3-cM (12.66-Mb) interval flanked by D19S928 and D19S420 cosegregated with the cataract locus. Lack of homozygosity further suggests that the cataract locus may lie in a 7-cM (4.3-Mb) interval flanked by D19S928 proximally and D19S425 distally. On fine mapping, a maximum lod score of 3.09 was obtained with D19S416 at {theta} = 0.

CONCLUSIONS. Linkage analysis identified a new locus for autosomal recessive congenital nuclear cataracts on chromosome 19q13 in a consanguineous Pakistani family.

Congenital cataracts are one of the major causes of vision loss in children worldwide1 2 and are responsible for approximately one third of blindness in infants. Congenital cataracts can occur in an isolated fashion or as one component of a syndrome affecting multiple tissues. Nonsyndromic congenital cataracts have an estimated frequency of 1 to 6 per 10,000 live births. They vary markedly in severity and morphology, affecting the nuclear, cortical, polar, or subcapsular parts of the lens or, in severe cases, the entire lens, with a variety of types of opacity. Congenital cataracts can lead to permanent blindness by interfering with the sharp focus of light on the retina during critical developmental intervals. In addition, congenital cataracts can provide insight into the biology of the lens as well as age-related cataract, which affects large parts of the aging population.

Approximately one third of congenital cataract cases are familial.3 Although autosomal dominant congenital cataract appears to be the most common familial form in the Western world,4 autosomal recessive and X-linked cataract also occur. To date, 21 loci have been identified for autosomal dominant cataract, and mutations in 13 of these genes have been reported.2 Fewer autosomal recessive congenital cataract loci and genes have been identified. Congenital recessive cataracts have been mapped to 6 loci residing on chromosomes 3p22-24.2, 6p23-24, 9q13-22, 16q21-22, 19q13.4, and 21q22.3.5 6 7 8 9 10 11 Of these, mutations in four genes: GCNT2, HSF4, LIM2, and CRYAA have been found.5 6 9 10 12 13

Herein, we report a consanguineous Pakistani family with multiple members affected by autosomal congenital recessive nuclear cataract. Initially, a genome-wide search including exclusion of known cataract loci was completed. Linkage analysis provided evidence of a new locus for autosomal congenital cataract on chromosome 19q13. The maximum lod score is obtained with D19S416 (Zmax = 3.09, at {theta} = 0), and the cataract locus cosegregates in a 14.3-cM (12.66-Mb) interval flanked by D19S928 and D19S420. Lack of homozygosity further suggests that the cataract locus may lie in a 7-cM (4.3 Mb) interval flanked by D19S928 proximally and D19S425 distally.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Clinical Ascertainment
A four-generation consanguineous Pakistani family with nonsyndromic congenital cataract was recruited to participate in a collaborative study between the Center of Excellence in Molecular Biology (Lahore, Pakistan) and the National Eye Institute (Bethesda, MD), to identify new disease loci causing inherited visual diseases. Institutional review board approval was obtained for this study from both centers. The participating subjects gave informed consent consistent with the tenets of the Declaration of Helsinki.

The family described in this study is from a remote village in the Punjab province of Pakistan. A detailed medical history was obtained by interviewing family members. Medical records of clinical examinations previously conducted with slit lamp biomicroscopy reported bilateral nuclear cataracts in all affected individuals for whom records were available. Cataracts were either present at birth or developed in infancy. The cataracts showed constant morphology, but varied in size. All affected individuals had cataract surgery in the early years of their lives, and hence no pictures of the lenses were available. Blood samples were collected from affected and unaffected family members. DNA was extracted by a nonorganic method, as described by Grimberg et al.14

Genotype Analysis
The initial genome scan was performed with 382 highly polymorphic fluorescent markers (PRISM Linkage Mapping Set MD-10; Applied Biosystems, Inc. [ABI], Foster City, CA) that have an average spacing of 10 cM. Multiplex polymerase chain reactions (PCR) were performed, as previously described.15 Briefly, each reaction was performed in a 5-µL mixture containing 40 ng genomic DNA, various combinations of 10 µM dye-labeled primers pairs, 0.5 µL 10x PCR buffer (GeneAmp Buffer II; ABI) 0.5 µL 10 mM dNTP mix, 2.5 mM MgCl2, and 0.2 U of Taq DNA polymerase (AmpliTaq Gold Enzyme, ABI). Amplification was performed in a PCR system (GeneAmp 9700; ABI). Initial denaturation was performed for 5 minutes at 95°C, followed by 10 cycles of 15 seconds at 94°C, 15 seconds at 55°C, and 30 seconds at 72°C and then 20 cycles of 15 seconds at 89°C, 15 seconds at 55°C, and 30 seconds at 72°C. The final extension was performed for 10 minutes at 72°C and followed by a final hold at 4°C. PCR products from each DNA sample were pooled and mixed with a loading cocktail containing size standards (HD-400; ABI) and loading dye. The resultant PCR products were separated on a 5% denaturing urea-polyacrylamide gel (Long Ranger; ABI) in a DNA sequencer (model 377; ABI) and analyzed by computer (Genescan, ver. 3.1 and Genotyper, ver. 2.1 software packages; ABI).

Linkage Analysis
Two-point linkage analyses were performed with the FASTLINK version of MLINK from the LINKAGE program package.16 17 Maximum lod scores were calculated using ILINK (all LINKAGE packages are provided in the public domain by the Human Genome Mapping Project Resources Centre, Cambridge, UK; http:www.hgmp.mrc.ac.uk). Autosomal recessive nuclear cataracts were analyzed as a fully penetrant trait with an affected allele frequency of 0.001. The marker order and distances between the markers were obtained from the Généthon database (http://www.genethon.fr/ provided in the public domain by the French Association against Myopathies, Evry, France) and the National Center for Biotechnology Information chromosome 19 sequence maps (http://www.ncbi.nlm.nih.gov/mapview/ provided in the public domain by National Center for Biotechnology, Bethesda, MD). For the initial genome scan, equal allele frequencies were assumed, whereas, for fine mapping, allele frequencies were estimated from 125 unrelated and unaffected individuals from the Punjab province of Pakistan.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Linkage to five known autosomal recessive cataract loci—3p23, 6p23-24, 9q13-p24, 19q14, and 21q22.3—was initially excluded by haplotype analysis using closely flanking markers (data not shown). A genome-wide scan yielded lod scores greater than 1.0 only for markers D1S498, D9S164, D19S226, and D19S414. Of these, D1S498 and D9S164 had closely flanking markers yielding large negative lod scores. D19S414 and D19S226 are adjacent markers in the MD-10 mapping set, yielding lod scores of 2.93 at {theta} = 0 and 1.24 at {theta} = 0.18, respectively. In addition, D19S221 on the proximal side of D19S414 supported linkage to this region with a maximum lod score of 0.29 at {theta} = 0.3.

Fine mapping using markers on chromosome 19 confirmed linkage to this region (Table 1) . The maximum lod scores in the region are 3.09 with D19S416 at {theta} = 0, 3.01 with D19S225 at {theta} = 0, 2.93 with D19S414 at {theta} = 0, and 2.65 with D19S213 at {theta} = 0. Obligate recombinants shown by lod scores of –{infty} at {theta} = 0 are obtained with the flanking markers D19S928 proximally and D19S420 distally. In addition, D19S425 and D19S220 yield a lod score of –1.33 at {theta} = 0 and –2.27 at {theta} = 0, respectively, strongly suggesting that the cataract locus lies in the D19S928 to D19S425 interval.


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  		TABLE 1. Two-Point Lod Scores of Chromosome 19q Markers

 
Visual inspection of the haplotypes of the markers used in fine mapping supports the linkage analysis, localizing the cataract locus to this region and placing it on chromosome 19q13 in the 14.3 cM (12.66 Mb) interval between D19S928 and D19S420 (Fig. 1) . There is a proximal recombination event at D19S928 in affected individual 13 and a distal recombination event at D19S420 in affected individual 11. In addition, lack of homozygosity at markers D19S425, D19S220, and D19S420 in affected individuals 11 to 14 of this consanguineous family suggests that the disease locus might be in the 7-cM (4.3-Mb) region bounded by D19S928 and D19S425. This lack of homozygosity is the source of the negative lod score for D19S425 and D19S220 on fine mapping (Table 1) .



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  		FIGURE 1. A simplified version of the pedigree of Pakistani family 60023. Squares: males; circles: females; filled symbols: affected individuals; double lines: indicates consanguinity; diagonal lines through symbols: deceased family members. The haplotypes analysis of 12 adjacent 19q microsatellite markers is shown with alleles forming the risk haplotype are shaded black, alleles cosegregating with cataracts but not showing homozygosity are shaded gray and alleles not cosegregating with cataracts are shown in white. SCN1B represents a single nucleotide polymorphism (SNP), a G-to-A transition in exon 3: c.412G->A of SCN1B (NM_199037).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
We report linkage of autosomal recessive nuclear cataracts in a consanguineous Pakistani family to markers on 19q13. The maximum lod score of 3.09 was obtained with D19S416 at {theta} = 0, and the cataract locus cosegregated with markers in a 14.3-cM (12.66-Mb) region of chromosome 19q13 flanked by D19S928 and D19S420. Lack of homozygosity further suggests that the cataract locus may lie in a 7-cM (4.3-Mb) D19S928 to D19S425 interval. Although the maximum lod score of 3.09 is only slightly higher than the traditional limiting value of 3.0, it represents the maximum value obtainable with this family. In addition, the lack of any lod scores above 1.5, except for marker D19S414, obtained in the remainder of the genome-wide scan and the large negative lod scores of markers flanking D1S498 and D9S164 (the two additional markers yielding lod scores greater than 1.0) provide additional support for localization of the cataract locus to 19q13. Finally, LIM2, a previously identified gene responsible for autosomal recessive cataract, was specifically excluded by linkage analysis and homozygosity mapping.

To date, six loci for congenital recessive cataract have been reported, and mutations have been found in genes at four of these loci: GCNT2 on chromosome 6, HSF4 on chromosome 16, LIM2 on chromosome 19, and CRYAA on chromosome 21. With the exception of {alpha}A-crystallin, these genes represent a rather different set than those in which mutations have been associated with autosomal dominant cataract. Most genes associated with dominant cataracts encode structural genes such as the highly expressed lens crystallin,18 19 20 cytoskeletal proteins such as the beaded filament protein BFSP2,21 and membrane proteins such as aquaporin0.22 Recessive cataracts appear more likely to be associated with enzymes such as GCNT2.10 Growth factors such as HSF423 or LIM26 have been shown to cause either autosomal dominant or recessive cataracts, depending on the type of mutation. The dual role of {alpha}-crystallin as both a structural crystallin and a chaperone may help to explain why mutations in this gene also can cause both autosomal dominant and recessive cataracts.

Nuclear cataract is the most common form of congenital cataract. Congenital nuclear cataracts have been associated both with autosomal dominant and autosomal recessive inheritance. To date, three autosomal dominant loci, 1pter-p36.13,24 2p12,25 and 12q13,26 and two autosomal recessive loci, 3p11 and 21q,5 have been identified in families with nuclear cataract. Mutations in CRYAA5 on chromosome 21 have been associated with nuclear cataracts. Moreover, mutations in ßB1-crystallin (CRYBB1),27 ßB2-crystallin (CRYBB2),18 {gamma}C-crystallin (CRYGC),19 and connexins Cx5028 and Cx4629 have been associated with nuclear pulverulent cataracts.

Crystallins make up 90% of soluble lens proteins and have an essential role in maintaining lens transparency. Another characteristic feature of the lens is its extensive system of low-resistance gap junctions between lens fiber cells. Structural proteins belonging to the connexin family make up the intercellular channels present in these gap junctions. Hence, together, crystallins and connexins are the most compelling candidates to screen for mutations for inherited cataract. No genes encoding crystallins or connexins are present in the 7-cM interval between D19S928 and D19S425. Other potential candidate genes present in this region are currently being screened for a possible role in the congenital nuclear cataract in this family. Identification of the specific mutation and gene associated with these cataracts will increase our understanding of lens biology and the nuclear cataract at a molecular level.


   Acknowledgements
 
The authors thank the family members who donated samples to make this work possible and Xiaodong Jiao for help throughout the work, suggestions during the linkage analysis, and preparation of the manuscript.


   Footnotes
 
3 Contributed equally to the work and therefore should be considered equivalent authors. Back

Supported in part by Higher Education Commission and Ministry of Science and Technology, Islamabad, Pakistan.

Submitted for publication August 6, 2004; revised October 25, 2004; accepted November 1, 2004.

Disclosure: S.A. Riazuddin, None; A. Yasmeen, None; Q. Zhang, None; W. Yao, None; M.F. Sabar, None; Z. Ahmed, None; S. Riazuddin, None; J.F. Hejtmancik, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: J. Fielding Hejtmancik, OGVFB/NEI/NIH, Building 10, Room 10B10, 10 Center Drive MSC 1860, Bethesda, MD 20892-1860; f3h{at}helix.nih.gov.


   References
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 Results
 Discussion
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