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Identification of a CRYAB Mutation Associated with Autosomal Dominant Posterior Polar Cataract in a Chinese Family

¹From the Center for Human Genome Research and College of Life Science and Technology and ⁴The Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, Peoples Republic of China; the ³People’s Hospital of Linyi, Shandong, Peoples Republic of China; and the ⁵Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

PURPOSE. A four-generation Chinese family with 13 members affected with autosomal dominant congenital posterior polar cataract was studied. The purpose of this study was to identify the disease-causing gene in the family and to validate that mutations in CRYAB, the B-crystallin gene, cause the congenital cataract.

METHODS. Linkage analysis was performed with a panel of microsatellite markers flanking candidate genetic loci for cataracts, including 14 known autosomal dominant congenital cataract (ADCC) genes. For mutation analysis, the complete coding region and exon-intron boundaries of CRYAB were sequenced with DNA from the proband. Single-strand conformation polymorphism (SSCP) analysis for exon 1 of CRYAB was performed in all family members and 200 normal control subjects.

RESULTS. The disease gene in the Chinese family was mapped to chromosome 11 in region q22-22.3 with a maximum lod score of 4.52. Direct DNA sequence of CRYAB revealed a heterozygous CT transition at nucleotide 58, resulting in a novel 58 CT (Pro20Ser) mutation. The Pro20Ser mutation cosegregated with all affected individuals and was not present in unaffected members in the family or in 200 normal control subjects. The mutation occurs at the evolutionarily conserved residue Pro20 in the N-terminal region of B-crystallin.

CONCLUSIONS. To date, only one CRYAB mutation has been associated with congenital isolated cataract. This study identified a second novel mutation in CRYAB in a large Chinese cataract family. Together, these results provide strong evidence that CRYAB is a pathogenic gene for congenital cataract.

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