A Novel Nonsense Mutation in CRYGC Associated with Autosomal Dominant Congenital Nuclear Cataract and Microcornea

Purpose: To report the identification of a novel nonsense mutation of CRYGC in a Chinese family with autosomal dominant congenital nuclear cataract and microcornea.Methods: We investigated a four-generation Chinese family with nuclear cataract and microcornea. The family resides in a relatively isolated region of North China. Informed consent in accordance with the Declaration of Helsinki and the Heilongjiang Institutional Review Board was obtained from all participants. Genomic DNA was prepared from blood leucocytes, genotyping was performed using more than 100 microsatellite markers for the known cataract candidate gene loci, and LOD scores were calculated using the LINKAGE programs. Mutation detection was carried out by sequencing candidate genes. Results:Suggestive evidence of linkage was detected at marker D2S325 (LOD score [Z] =2.29, recombination fraction [θ] =0.0), which closely flank the γ-crystallin gene (CRYGA-CRYGD) cluster on chromosome 2q33.3-q34. Direct sequencing of the candidate CRYGA-CRYGD gene cluster revealed a G->A transversion in exon 3 of CRYGC, which cosegregated with cataract in the family and was not observed in 100 normal controls. This single-nucleotide change was predicted to introduce a translation stop codon at tryptophane 157 (W157X). Conclusions: This is the first report that a novel nonsense mutation in CRYGC caused congenital nuclear cataract and microcornea in a Chinese family. Our finding expands the spectrum of CRYGC mutations in association with congenital cataract, and confirms the role of γ-crystallin in the pathogenesis of congenital nuclear cataract. The association of microcornea with congenital cataract in all affected individuals further underlines the role of the CRYGC in lens and anterior ocular development.