Cataract 22, Multiple Types

A number sign (#) is used with this entry because of evidence that multiple types of cataract (CTRCT22) are caused by heterozygous or homozygous mutation in the beta-B3 crystallin gene (CRYBB3; 123630) on chromosome 22q11.

Description

Mutations in the CRYBB3 gene have been identified in families with cataract, described as congenital nuclear cataract with cortical riders, nuclear, posterior polar, anterior polar, and cortical.

The preferred title/symbol of this entry was formerly 'Cataract, Congenital Nuclear, Autosomal Recessive 2; CATCN2.'

Clinical Features

Riazuddin et al. (2005) described 2 consanguineous Pakistani families from the Punjab region with autosomal recessive nonsyndromic congenital nuclear cataract with cortical riders.

Reis et al. (2013) studied a large 4-generation Caucasian Italian family segregating autosomal dominant bilateral congenital cataract with incomplete penetrance. The specific type of cataract varied, including posterior polar cataract in 2 individuals, nuclear cataract in 2, and anterior polar plus cortical cataract in 1. In 4 patients, cataracts were diagnosed at birth, and in 1 patient, the diagnosis was made at 1 year of age. Two affected individuals also had glaucoma. Two obligate carriers who were last examined at ages 46 and 70 years, respectively, showed no evidence of cataract.

Mapping

Riazuddin et al. (2005) performed a genomewide scan of affected and unaffected members of 2 consanguineous Pakistani families with congenital cataract and obtained maximum lod scores of 2.67 and 2.77 for one family and 2.02 and 2.04 for the other family for markers D22S539 and D22S315, respectively. The linked region, 22.7 cM flanked by markers D22S420 and D22S1163, contained the beta-crystallin gene cluster.

Inheritance

The transmission pattern of cataract in the family reported by Riazuddin et al. (2005) was consistent with autosomal recessive inheritance.

The transmission pattern of cataract in the family reported by Reis et al. (2013) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of 2 consanguineous Pakistani families segregating nonsyndromic congenital cataract mapping to chromosome 22q11, Riazuddin et al. (2005) sequenced the beta-crystallin genes in this region and identified a missense mutation in the CRYBB3 gene (G165R; 123630.0001) (123630.0001) that cosegregated with the disease in both families. Molecular modeling predicted changes in electrostatic potential that would be expected to reduce the stability of the fourth Greek key motif, and hence the entire protein, dramatically.

In 5 affected members of a large 4-generation Caucasian Italian family segregating multiple types of autosomal dominant congenital cataract with incomplete penetrance, Reis et al. (2013) identified heterozygosity for a missense mutation in the CRYBB3 gene (V194E; 123630.0002). The mutation was also detected in 1 unaffected family member, who was last examined at 34 years of age and showed no evidence of cataract. The mutation, which was not found in 12,999 control chromosomes from the Exome Variant Server database, results in the substitution of a highly conserved hydrophobic valine with hydrophilic glutamic acid; it was predicted to cause destabilization of the domain structure of the Greek key motif IV and to affect CRYBB3 protein folding.