Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628502
Title: Investigating genotype-phenotype correlations and potential therapies for laminopathies
Author: Scharner, Juergen
ISNI:       0000 0004 5366 7036
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2014
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Abstract:
Laminopathies are a heterogeneous group of diseases associated with mutations in A-type lamins, which together with B-type lamins, form the nuclear lamina: a proteinaceous network underlying the nuclear membrane. A-type lamins are encoded by the LA1NA gene, and more than 300 mutations have been described, associated with more than 16 phenotypes. The majority of mutations affect striated muscle to cause Emery-Dreifuss muscular dystrophy (EDMD) or cardiomyopathy, while others result in lipodystrophy, neuropathy or premature ageing syndromes. However, clear genotype-phenotype correlations are not established, the pathogenic mechanisms are little understood and therapies are lacking. -- This thesis first explores genotype-phenotype for LMZV/4 mutations and makes correlations by characterising both physical-chemical properties of the amino-acid change, and position in the 3D structure of lamin A. LMNsl mutations associated with muscular dystrophies, premature ageing disorders and lipodystrophies clustered in the Ig-fold domain of lamin A and resulted in a similar change in charge, suggesting that modification of specific protein-protein interactions contribute to different phenotypes. -- Next, I investigated the effects of four pathogenic EDMD mutations on nuclear morphology, nuclear protein distribution and myogenic cell function. I found that some mutations led to severe nuclear deformations and mislocalisation of lamin B, while others caused accumulation of lamin A-positive nuclear foci. Myogenic differentiation was mildly affected by some mutant lamin A species. -- Finally, I describe a series of proof-of-principle experiments investigating a potential therapeutic intervention for laminopathies. A lamin A variant with a deletion corresponding to regions encoded by exon 5, removing 42 amino acids in the central rod domain, localised correctly.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.628502  DOI: Not available
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