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Title: A GFPT1 deficient mouse model of congenital myasthenic syndrome
Author: Issop, Yasmin
ISNI:       0000 0004 7233 2733
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2017
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Congenital myasthenic syndromes (CMS) are inherited disorders characterised by fatigable muscle weakness resulting from impaired transmission at the neuromuscular junction (NMJ). CMS occur due to mutations in genes encoding proteins responsible for maintaining the structure and function of the NMJ. Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway which yields precursors required for protein and lipid glycosylation. Mutations in GFPT1 and genes downstream of this pathway are pathogenic for CMS. One hypothesis is that hypoglycosylation of NMJ proteins results in defective neurotransmission. The aim of this study is to generate and characterise a GFPT1 deficient mouse model of CMS. One of the challenges we face is the viability of Gfpt1 knockout mice. Here we generate a novel muscle-specific GFPT1 knockout mouse model using Cre/loxP technology. We demonstrate that a deficiency of GFPT1 in muscle only, is sufficient for causing a CMS phenotype. Our model recapitulates many aspects of the phenotype observed in patients with GFPT1-related CMS. Mutant mice display early changes in the morphology of postsynaptic components of the NMJ, which are accompanied by presynaptic alterations. They later develop a myopathic phenotype and formation of tubular aggregates. We further identify proteins in skeletal muscle that are differentially regulated because of GFPT1 deficiency. Our data demonstrates a critical role for GFPT1 in the development of the NMJ, neurotransmission, and skeletal muscle integrity. The muscle-specific GFPT1 deficient mouse model allows us to investigate the implications of not only GFPT1 mutations, but may also give us an insight into the pathophysiological consequences of mutations in genes downstream of GFPT1, which also result in hypoglycosylation. This model has the potential to enhance our understanding of current drug therapies, and to drive forward the development of new compounds which can be implemented in the clinic.
Supervisor: Not available Sponsor: Medical Research Council ; Barbour Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available