Bitner-Glindzicz, Maria A.K.; (1996) Molecular genetics of X-linked deafness. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Non-syndromic X-linked deafness is genetically heterogeneous but clinical and radiological studies have defined a single phenotype with abnormal cochlear morphology which maps to Xq13-21, as well as families with normal radiology who also map to this region. The aim of this study in molecular genetics of X-linked deafness was to identify the gene(s) responsible in order to be able to offer families accurate genetic counselling based on mutation analysis, and to gain some insight into what kind of genes when mutated, cause non-syndromic hearing loss. A linkage study was carried out using three polymorphic microsatellite repeats from Xq21 and showed that families with and without abnormal cochlear morphology map to this region. The microsatellite at DXS995 achieved a maximum lod score of 10.73 at ? = 0. Families with and without developmental cochlear abnormality could not be distinguished by linkage analysis. Additional patients were ascertained, phenotyped and characterised by deletion studies including dosage. The critical region for the disease gene was reduced to approximately 150kb and the entire region was cloned in cosmids. The distal breakpoints of the defining patients were identified. A CpG island and evolutionarily conserved fragments were identified in these cosmids and a candidate gene, the human homologue of the mouse gene brain 4, now called POU3F4, was mapped back to these cosmids. Two point mutations were identified in the candidate gene; a four base-pair deletion in the homeodomain of the predicted protein, and a missense mutation in a highly conserved amino acid residue, which was found to be a de novo mutation. Not all families with the characteristic morphology have mutations in POU3F4 and two British patients have microdeletions proximal to, but not encompassing POU3F4, leaving the precise reason for their deafness unexplained. None of the families with normal cochlear radiology have mutations in POU3F4, or chromosomal aberrations which affect its expression, implying the presence of another deafness gene in this region.

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