A new beta A1-crystallin splice junction mutation in autosomal dominant cataract

PURPOSE. To map the locus for autosomal dominant cataracts (ADCs) in a Braz ilian family using candidate gene linkage analyses, describe the clinical v ariability, and identify potential mutations in the human beta A1-crystalli n gene (CRYBA1), a candidate gene identified through linkage studies demons trating cosegregation with markers on chromosome 17. METHODS. Members of a Brazilian family with ADC were studied. Clinical exam inations and linkage analyses with polymerase chain reaction (PCR) polymorp hisms of 22 anonymous markers and 2 within the neurofibromatosis type 1 gen e were performed; two-point lod scores were calculated. DNA sequences of al l 6 exons and 12 exon-intron boundaries of the beta A1-crystallin gene, a p roximal candidate gene mapped to 17q11.1-q12 in one unaffected and two affe cted individuals, were screened and new variants assessed for cosegregation with the disease. RESULTS. Affected individuals exhibited variable expressivity of pulverulen t 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 we re 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 interven ing recombination. The only known candidate gene in these regions was beta A1-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 causat ive mutation. CONCLUSIONS. An ADC locus was mapped in a Brazilian family with variable ex pressivity to either 17q23.1-23.2 or 17q11.1-12 based on linkage analyses. Analyses of DNA sequences of the beta A1-crystallin gene in this family rev ealed three new variants, one of which is within a donor splice junction an d cosegregates with affected members.