Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans

Abstract

Congenital cataracts are an important cause of bilateral visual impairment in infants. In a four-generation family of English descent, we mapped dominant congenital posterior polar cataract to chromosome 11q22-q22.3. The maximum LOD score, 3.92 at recombination fraction 0, was obtained for marker D11S898, near the gene that encodes crystallin alpha-B protein (CRYAB). By sequencing the coding regions of CRYAB, we found in exon 3 a deletion mutation, 450delA, that is associated with cataract in this family. The mutation resulted in a frameshift in codon 150 and produced an aberrant protein consisting of 184 residues. This is the first report of a mutation, in this gene, resulting in isolated congenital cataract.

Figure 1

Direct illumination (A) and retroillumination (B) of posterior polar cataract observed in the 11-year-old boy (V:1) in the family with CPP2.

Figure 2

Family with CPP2. Square symbols denote males; circles denote females; affected individuals are denoted by black symbols. Autosomal dominant inheritance is suggested both by the presence of affected males and females in each generation and by male-to-male transmission.

Figure 3

Sequence analysis of CRYAB in an unaffected individual (A) and an affected individual (B), both from the family with CPP2.

Figure 4

Protein alignment depicting similarity of human αB- and αA-crystallin with those of mouse, cow, rabbit, and chicken. Human αB-crystallin shows the highest homology, over its entire length, to αB-crystallins of rabbit, cow, mouse, and chicken, with identity scores of 98%, 97%, 97%, and 76%, respectively. Human αB-crystallin has 55% amino acid identity with αA-crystallin of human and of cow. Amino acids that exhibit complete identity across species are boxed. The aberrant protein produced as a result of the deletion mutation, 450delA, is shown with its 35 novel residues (blue) after the 149th residue of the wild- type αB-crystallin (arrow). The amino acid residue mutated (R120G [red]) in desmin-related myopathy is also shown.