Addison, P.K.F.; (2006) Clinical, molecular, genetic and functional studies on inherited human cataracts. Doctoral thesis , University of London.

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Abstract

Cataracts, the commonest cause of blindness in the world, may be broadly divided into adult onset and childhood onset. Some childhood cataracts are present from birth (congenital cataracts). About one third of congenital cataracts occurring as isolated abnormalities, and not part of a syndrome, are inherited. Full clinical examination was performed on individuals from families with inherited cataracts. DNA was extracted from peripheral blood samples. Linkage analysis was performed in three large families. Key individuals were examined from two of these families with autosomal dominant congenital cataract (ADCC). In one of the families, cataract was linked and linkage refined to a region encompassing the transcription factor gene, PITX3, known to be associated with cataracts and anterior segement mesenchymal dysgenesis (ASMD). Both families were found to have the same mutation in this gene, which segregated with disease and was absent in control individuals. The phenotype in these families, posterior polar cataract with or without ASMD, is different from that previously reported for this mutation and shows both inter- and intra-familial variability. Autosomal dominant (AD) zonular pulverulent cataract in a third large family was linked to the connexin 46 gene (CX46), known to be associated with cataracts. Sequence analysis identified a novel mutation in this gene which segregated with disease in the family and was absent in control individuals. Wild type and mutant constructs of CX46 were prepared and expressed in human HeLa cells. These studies demonstrated that the mutation does not affect trafficking of the protein to the cell membrane. Individuals from twenty-one farther families with inherited cataract were examined clinically. Their DNA samples were added to the existing panel for candidate gene screening.

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