CRYGD gene analysis in a family with autosomal dominant congenital cataract: evidence for molecular homogeneity and intrafamilial clinical heterogeneity in aculeiform cataract.

PURPOSE To present a previously unreported four generation affected Mexican pedigree with congenital hereditary aculeiform cataract caused by a mutation in the gammaD-crystallin (CRYGD) gene. METHODS A four generation family with 14 available members of whom 8 were affected was analyzed. Interventions included complete ophthalmological examination, cataract phenotype characterization, PCR amplification, and automated DNA sequencing of the 2 exons and exon/intron junctions of the CRYGD gene. RESULTS A heterozygous missense mutation consisting of a G to A transition at nucleotide position 411 in exon 2 that predicts an Arg to His replacement in residue 58 (R58H) of the CRYGD protein was demonstrated. Intrafamilial clinical heterogeneity was observed as one affected member exhibited a coral-like cataract. CONCLUSIONS The R58H mutation described in this Mexican family is identical to that demonstrated previously in three unrelated families with aculeiform cataract, suggesting that this type of cataract has a specific molecular basis represented by the Arg to His change at residue 58 of CRYGD. However, intrafamilial clinical heterogeneity associated with this mutation can occur as evidenced by the identification of a subject in this family exhibiting a coral-like cataract, a phenotype classically distinguished from aculeiform cataract. To our knowledge, this is the first example of phenotypic heterogeneity associated with the Arg 58 His CRYGD mutation.