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Title: Studies of the molecular basis of epidermolysis bullosa simplex
Author: Smith, Frances J. D.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1994
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The aim of this project was to investigate the possible mechanisms for intraepidermal blistering. Attention was concentrated on locating mutations in the genes encoding keratins K5 and K14, the putative defective genes, in five families affected by the Weber-Cockayne form of EBS, characterised by blisters predominantly on the hands and feet. In four of the five families examined, single nucleotide substitutions resulting in an amino acid change were identified. In two families, mutations were identified in the central non-helical L12 linker domain, one in keratin 5 and the other in keratin 14. This was surprising as relatively little is known about this region, and it was not considered to be particularly important in keratin filament assembly or network formation. Another mutation has been reported in this region in keratin 14 in a family with EBS-Koebner characterised by moderate and generalised blistering. Although just two residues away from the mutation reported here, the difference in severity of the resulting phenotypes emphasises the contribution of individual residues to the overall functioning of the keratin filament network. In the third family a mutation was identified in the 1A domain of keratin 5, at the carboxy terminal of this domain. In the fourth family a tentative mutation was identified near the centre of the 2B domain of keratin 14. Extensive sequencing of both K5 and K14 DNA from members of the fifth family did not identify any sequencing discrepancies and genetic linkage analysis suggested that the disease phenotype in this family was linked to the type I keratins. It is possible though, that mutations in minor basal cell keratins such as keratin 15, or in a keratin associated protein, could lead to the same clinical phenotype. Keratin mutations have now been identified in another bullous disorder, bullous congenital ichthyosiform erythroderma, in the supra basal keratins K1 and K10.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available