Tyson, Jessica Grace; (1999) Molecular genetic studies of deafness. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of this work on the molecular genetics of deafness was to study the molecular basis of deafness in several families with non-syndromic and syndromic forms of deafness, including X-linked deafness and autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). From one of the first studies on mapping of genes for X-linked deafness, it was shown that X-linked deafness, although very rare, is genetically heterogeneous. Linkage analysis of a single large family identified a novel locus for X-linked deafness, DFN2. Several candidate genes, including COL4A5, DDP and Diaphanous X, were screened. A major locus for X-linked deafness, DFN3, has previously been identified at Xq13-q21. Deafness in most of the families mapping to this region is accounted for by mutation in the transcription factor gene, POU3F4. However, the remaining families have microdeletions proximal to, but not encompassing, the POU3F4 coding region, leaving the precise reason for their deafness unexplained. POU3F4 expression was studied in these individuals to determine whether there is a position effect on the POU3F4 gene, or a second gene proximal to it. Homozygosity mapping in conjunction with screening of candidate loci identified a new locus for the cardioauditory syndrome, JLNS. A positional candidate approach identified IsK as the causative gene. An IsK mutant construct has been created to study the mechanism of action of this mutation. During the course of this work, the potassium channel gene KVLQT1 was implicated in JLNS. Haplotype analysis of 12 additional JLNS families in this study was consistent with mutation in KVLQT1. Exons of the KVLQT1 gene were identified and primers designed for use with genomic DNA. Novel mutations were identified, confirming the role of KVLQT1 in JLNS and demonstrating that KVLQT1 is the major locus for this syndrome.

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