Refining Genotype-Phenotype Correlation In Epidermolysis Bullosa

Student thesis: Doctoral ThesisDoctor of Philosophy


Dystrophic epidermolysis bullosa results from mutations in COL7A1 that encodes collagen VII, the major component of anchoring fibrils. General paradigms have emerged attributing dominant DEB to heterozygous glycine substitutions and recessive DEB to nonsense, frameshift or splice site mutations on both COL7A1 alleles. Several aspects of the genotype-phenotype heterogeneity encountered in DEB remain unexplained, although genetic, epigenetic and environmental modulators have been implicated. In this thesis, various aspects of DEB were studied, in a bid to refine genotype-phenotype correlation. A detailed analysis of missense GS and non-GS mutations identified 57 novel mutations and was in-keeping with the general established paradigms. Unique clinical entities such as EB-pr and BDN were studied. The role of the matrix metalloproteinase-1 promoter polymorphism, -1607 1G/2G, on disease modification in EB-pr was explored, but was shown to be an unlikely modulator. A large study of BDN, highlighted that intracytoplasmic retention of collagen VII and stellate bodies were not exclusive to BDN and can be associated with various subtypes of DEB, non-EB cases and normal skin. The first case of revertant mosaicism in DEB was studied revealing intragenic cross-over as the underlying mechanism. Finally, intradermal injection of allogeneic fibroblasts was shown to result in increased and sustained expression of COL7A1 possibly through the upregulation of HB-EGF. Recognition of disease modifiers in DEB and refinement of genotype–phenotype correlation will not only further our understanding of DEB but will have implications on diagnosis, counselling and prognosis through patient specific and targeted therapy.
Date of Award2017
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJohn McGrath (Supervisor) & Stephen Minger (Supervisor)

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