Investigating the mechanisms and modifiers of disease resulting from mutations in COL4A1 and COL4A2

Fleming, Lauren Kaye (2019) Investigating the mechanisms and modifiers of disease resulting from mutations in COL4A1 and COL4A2. PhD thesis, University of Glasgow.

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Haemorrhagic stroke accounts for 15% of adult stroke. Mutations within COL4A1 and COL4A2 (collagen IV alpha chain 1/2) cause familial forms of cerebrovascular disease, including intracerebral haemorrhage (ICH). Collagen IV is a major component of the basement membrane and provides structural support within blood vessel walls. Cerebrovascular disease caused by mutations inCOL4A1/COL4A2 exhibit reduced penetrance, indicating that genetic modifiers can prevent disease development, and their identification will highlight putative therapeutic targets.
We aimed to shed light on the underlying molecular mechanism of COL4A1/COL4A2 disease and the identity of genetic modifiers by performing proteomics analysis (LC/MS) on cells from both an ICH patient and his unaffected father who both carry the same pathogenic COL4A2+/G702D mutation. Candidate modifier pathways were then verified using functional analyses. Pharmacological mimicking of one particular candidate modifier pathway in patient dermal fibroblasts revealed that the molecular phenotype associated with disease severity, namely COL4A2 accumulation within the ER, could be reduced.
Lastly, there is a growing pool of patients presenting with disease phenotypes resultant from atypical mutations in COL4A1/COL4A2, however, molecular analysis of these individuals has thus far been largely unreported. Through collaborations, we gained access to fibroblast samples from patients with various COL4A1/COL4A2 mutations who exhibit cerebral small vessel disease, including a different glycine mutation, 3’UTR mutations in COL4A1 and a 13q33.2q34 duplication. Investigation of their pathomolecular mechanisms and efficacy of our candidate modifier on those mutations in which a downstream intracellular phenotype occurs, was performed.
In summary, BM fragility owed to mutations in COL4A1 and COL4A2 is likely mediated by multiple independent molecular influences. Further studies unpicking the relative contributions of these processes may shed light on the pleiotropic effects of COL4A1/COL4A2 mutations in human disease, which will enable the identification of therapeutic agent that specifically targets one pathway, without indirectly aggravating other pathways, to achieve the greatest therapeutic potential.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Due to copyright issues the full text of this thesis will not be uploaded at the end of the embargo period, 4 March 2022. An edited version will be made available post embargo.
Keywords: Basement membrane, COL4A1, COL4A2, extracellular matrix, genetic disease.
Subjects: Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Supervisor's Name: Van Agtmael, Dr. Tom
Date of Award: 2019
Embargo Date: 4 March 2022
Depositing User: Ms Lauren Fleming
Unique ID: glathesis:2019-41043
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 05 Mar 2019 10:11
Last Modified: 05 Mar 2020 22:18
Thesis DOI: 10.5525/gla.thesis.41043

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