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1 From the Departments of Ophthalmology and 5 Pharmacology, and 2 The Children’s Hospital, the University of Colorado School of Medicine; the 3 Eleanor Roosevelt Institute, Denver, Colorado; the 4 Department of Pediatrics, University of California, Irvine; and the 6 Department of Ophthalmology, University of Curitiba School of Medicine, Brazil.
PURPOSE. To map the locus for autosomal dominant cataracts (ADCs) in a Brazilian family using candidate gene linkage analyses, describe the clinical variability, and identify potential mutations in the human ßA1-crystallin gene (CRYBA1), a candidate gene identified through linkage studies demonstrating cosegregation with markers on chromosome 17.
METHODS. Members of a Brazilian family with ADC were studied. Clinical examinations and linkage analyses with polymerase chain reaction (PCR) polymorphisms of 22 anonymous markers and 2 within the neurofibromatosis type 1 gene were performed; two-point lod scores were calculated. DNA sequences of all 6 exons and 12 exon–intron boundaries of the ßA1-crystallin gene, a proximal candidate gene mapped to 17q11.1-q12 in one unaffected and two affected individuals, were screened and new variants assessed for cosegregation with the disease.
RESULTS. Affected individuals exhibited variable expressivity of pulverulent opacities in the embryonal nucleus and sutures; star-shaped, shieldlike, or radial opacities in the posterior embryonal nucleus; and/or midcortical opacities. All known loci for ADC in this family on chromosomes 1 and 13 were excluded. A positive lod score on chromosome 17 was calculated. This ADC locus was mapped to two potential regions on the long arm with an intervening recombination. The only known candidate gene in these regions was ßA1-crystallin. Three previously unreported single nucleotide variants were found in this gene, one in the donor splice junction site of intron C. This variant was found in all affected members and is presumed to be the causative mutation.
CONCLUSIONS. An ADC locus was mapped in a Brazilian family with variable expressivity to either 17q23.1-23.2 or 17q11.1-12 based on linkage analyses. Analyses of DNA sequences of the ßA1-crystallin gene in this family revealed three new variants, one of which is within a donor splice junction and cosegregates with affected members.
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