Initiation codon mutation in betaB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract

Abstract

Purpose: To identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children.

Methods: An autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing.

Results: The SNP microarray data demonstrated a 24.96 Mb region of homozygosity at 22q11.21-22q13.2 which was confirmed by microsatellite marker analysis. The candidate target region contained the beta-crystallin gene cluster and direct sequencing in affected family members revealed a novel mutation in CRYBB1 (c.2T>A; p.Met1Lys).

Conclusions: To our knowledge this is the first case of an initiation codon mutation in a human crystallin gene, and only the second report of a CRYBB1 mutation associated with autosomal recessive congenital cataracts. In addition, although a number of genetic causes of autosomal dominant pulverulent cataracts have been identified (including CRYBB1) this is the first gene to have been implicated in autosomal recessive nuclear pulverulent cataract.

Figure 1

Cataract phenotype of family. A: Left eye retroillumination view and B: left eye slitlamp view of patient II:3. C: Left eye retroillumination view and D: left eye slit lamp view of patient II:5. E: Left eye retroillumination view and F: left eye slit lamp view of patient II:6. G: Right eye slit lamp view and H: left eye slit lamp view of patient II:4.

Figure 2

Cataract pedigree and haplotype analysis. Pedigree and haplotype analysis of Somali cataract family shows segregation of microsatellite markers surrounding β-crystallin cluster on chromosome 22.

Figure 3

CRYBB1 mutation. In top row is the wildtype sequence in a control; in the middle row is a heterozygous CRYBB1 mutation (c.2T>A) in the mother; and at the bottom is a homozygous CRYBB1 variant (c.2T>A) in an affected individual.