Mackay, Donna Siobhain; (1998) Identification of connexin gene mutations in a linkage study of inherited cataract. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Autosomal dominant cataract (ADC) is a clinically and genetically heterogeneous disease. Families with ADC were collected from Moorfields Eye hospital, London and separated into eight phenotypic groups. The most common phenotypic group was the pulverulent cataract, an opacity dust-like in nature. The aim of this study was to identify the genes responsible for the pulverulent phenotype. Genetic linkage analysis using microsatellite markers was used to perform a whole genome search to map a new locus (CZP3) to chromosome 13q, near the candidate gene GJA3. Families A and E mapped to CZP3. The entire coding sequence of the human GJA3 gene was identified so that mutation analysis could be performed. Analysis of the coding region in family A identified an A G transition, predicting an asparagine to serine change at codon 63 (N63S) and introducing a Mwo I restriction site that segregated with the disease. Sequence analysis in family E showed the insertion of a C at position 1137 (1137insC), predicted to cause a frameshift leading to the extension of encoded peptide by 31 amino acids, creating a novel stretch of 87 amino acids at the end of the peptide. This sequence change caused the introduction of a Bst XI restriction site that segregated with the disease. Families O and C were identified as descendants of the original family used in the identification of the first locus for ADC, CZP1. Microsatellite markers were used to genetically refine CZP1 to chromosome 1q21, near the candidate gene GJA8. Mutation screening of this gene identified a C?T transition segregating with the disease in these two families, predicting a proline to serine change at position 88 (P88S). This sequence change caused the introduction of a Mnl I restriction site. A third family (CCT) mapped to CZP1. Mutation analysis identified a G?A transition in codon 48 changing an to a lysine (E48K) and removing a Fok I restriction site. This study has shown that mutations in two connexins known to be expressed in the lens fibre cells GJA3 and GJA8, are involved in ADC. This is the first time that connexins in the lens have been implicated in human cataract, suggesting that these proteins have important function in maintaining the normal lens transparency.

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