Identification of a Novel Oligomerization Disrupting Mutation in CRYΑA Associated with Congenital Cataract in a South Australian Family

ABSTRACT Congenital cataract is a heterogeneous disorder causing severe visual impairment in affected children. We screened four South Australian families with autosomal dominant congenital cataract for mutations in 10 crystallin genes known to cause congenital cataract. We identified a novel segregating heterozygous mutation, c.62G>A (p.R21Q), in the CRYΑA gene in one family. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of the high‐molecular‐weight oligomers seen in the lens material of an unaffected individual. We conclude that the p.R21Q mutation, which is located in the highly conserved and structurally significant N‐terminal region of the protein, is responsible for the cataract phenotype observed in the family as this mutation likely reduces the formation of the functional oligomeric alpha‐crystallin. A p.R21Q mutation in the alpha‐crystallin A gene was shown to segregate with a nuclear lamellar congenital cataract of variable severity in an Australian family. This mutation appears to affect the ability of the CRYAA protein to form the high molecular weight oligomers essential to its chaperone function.