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Title: Functional implications of Fkrp deficiency
Author: Whitmore, Charlotte
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Mutations in FKRP (fukutin related protein) are associated with the dystroglycanopathies, a group of neuromuscular conditions with a spectrum of clinical phenotypes. However, as there is currently no method for detecting Fkrp expression, or measuring its activity, the function has not been fully elucidated. Here, the implications of Fkrp deficiency have been evaluated to provide further insight into the role of this protein. In the muscle, brain and eye (three tissues severely affected in dystroglycanopathy patients), it was shown using the FKRPKD mouse, with its global reduction in Fkrp expression of 80%, that basement membrane deposition was perturbed in the muscle fibres of the tongue, the pial basement membrane of the cortex and both ocular basement membranes (Bruch's and the inner limiting membrane). It was also demonstrated that these basement membrane defects were associated with altered, reduced glyosylation of α-dystroglycan, and that these changes had marked consequences for cortical and retinal lamination. Interestingly, this investigation highlighted an important, previously undescribed, role for glycosylated α-dystroglycan in early brain and retinal development. To investigate the effects of reduced Fkrp expression on muscle, a novel mouse (FKRPMD) was generated, with had restored f Fkrp expression in the central nervous system. This mouse developed a mild dystrophic pathology, associated with defects in basement membrane deposition and altered, reduced glycosylation of α-dystroglycan. LARGE upregulation has been published as a successful short-term therapeutic strategy in other preclinical dystroglycanopathy models, but none with impaired Fkrp expression. Here, it was demonstrated that long-term LARGE upregulation exacerbated dystrophic pathology in the FKRPMD mouse, despite increased α-dystroglycan glycosylation. In combination, this work highlights the critical role of Fkrp for basement membrane deposition in muscle, brain and eye, identifies the downstream consequences for these three organs and highlights that LARGE upregulation as a therapeutic strategy requires further investigation.
Supervisor: Brown, Susan ; de Belleroche, Jackie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available