A new heterozygous mutation in the stop codon of CRYAB (p.X176Y) is liable for congenital posterior pole cataract in a Chinese family.

Background: The present study aims to identify the underlying genetic defects in a Chinese family with autosomal dominant congenital cataracts (ADCC). Methods: Detailed family histories and clinical data were recorded. Targeted exome sequencing of 54 known cataract-associated genes combined with high-throughput next-generation sequencing was conducted followed by Sanger sequencing and bioinformatic analysis to identify the causative gene lesion for the family. Results: A four-generation Chinese family with posterior pole type cataract were enrolled. Enrichment of targeted genes revealed a new heterozygous p.X176Y mutation in the stop codon of alpha B-crystallin (CRYAB) gene, which resulted in the loss of the stop codon and prolongation of the mutant protein by 19 amino acid residues (p.X176Yfs19*). Sanger sequencing showed complete co-segregation with the disease. The elongated mutant protein was predicted to be pathogenic by forming new alpha-helix and random-coil in the secondary structure as well as producing an extended strand in the tertiary structure, potentially leading to increased hydrophobicity and reduced protein stability. Conclusions: Our report added a new mutation in the spectrum of congenital cataracts. The data suggested that X176 residue in the COOH-terminal is of crucial importance for the alpha B-crystallin protein function which was valuable for further study of the pathogenesis of congenital cataracts.

Automated summary

The study identified a new heterozygous p.X176Y mutation in the stop codon of the alpha B-crystallin (CRYAB) gene, leading to an elongated mutant protein and potentially increased pathogenicity. This mutation added to the spectrum of congenital cataracts, emphasizing the importance of the X176 residue in the COOH-terminal for alpha B-crystallin protein function.