GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice

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• dc.contributor.author Issop, Yasmin
• dc.contributor.author Hathazi, Denisa
• dc.contributor.author Khan, Muzamil Majid
• dc.contributor.author Rudolf, Rüdiger
• dc.contributor.author Weis, Joachim
• dc.contributor.author Spendiff, Sally
• dc.contributor.author Slater, Clarke R.
• dc.contributor.author Roos, Andreas
• dc.contributor.author Lochmüller, Hanns
• dc.date.accessioned 2019-11-20T08:48:38Z
• dc.date.available 2019-11-20T08:48:38Z
• dc.date.issued 2018
• dc.description.abstract 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 other genes downstream of this pathway cause congenital myasthenic syndrome (CMS) characterized by fatigable muscle weakness owing to impaired neurotransmission. The precise pathomechanisms at the neuromuscular junction (NMJ) owing to a deficiency in GFPT1 is yet to be discovered. One of the challenges we face is the viability of Gfpt1-/- knockout mice. In this study, we use Cre/LoxP technology to generate a muscle-specific GFPT1 knockout mouse model, Gfpt1tm1d/tm1d, characteristic of the human CMS phenotype. Our data suggest a critical role for muscle derived GFPT1 in the development of the NMJ, neurotransmission, skeletal muscle integrity and highlight that a deficiency in skeletal muscle alone is sufficient to cause morphological postsynaptic NMJ changes that are accompanied by presynaptic alterations despite the conservation of neuronal GFPT1 expression. In addition to the conventional morphological NMJ changes and fatigable muscle weakness, Gfpt1tm1d/tm1d mice display a progressive myopathic phenotype with the presence of tubular aggregates in muscle, characteristic of the GFPT1-CMS phenotype. We further identify an upregulation of skeletal muscle proteins glypican-1, farnesyltransferase/geranylgeranyltransferase type-1 subunit α and muscle-specific kinase, which are known to be involved in the differentiation and maintenance of the NMJ. The Gfpt1tm1d/tm1d model allows for further investigation of pathophysiological consequences on genes and pathways downstream of GFPT1 likely to involve misglycosylation or hypoglycosylation of NMJs and muscle targets.
• dc.description.sponsorship This work was supported by a studentship of The Barbour Foundation and the Medical Research Council (UK) to Y.I.; the Medical Research Council as part of the MRC Centre for Neuromuscular Diseases (reference G1002274, grant ID 98482), a Wellcome Trust Pathfinder Award (201064/Z/16/Z) to H.L.; the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 305444 (RD-Connect) and 305121 (NeurOmics) to H.L.; an award from the French Muscular Dystrophy Association (AFM-Téléthon) No. 20870 to H.L.; the German Research Fund (RU923/8-2) to R.R., and by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Senatsverwaltung für Wirtschaft, Technologie und Forschung des Landes Berlin, and the Bundesministerium für Bildung und Forschung. Funding to pay the Open Access publication charges for this article was provided by The Medical Research Council (MRC).
• dc.format.mimetype application/pdf
• dc.identifier.citation Issop Y, Hathazi D, Khan MM, Rudolf R, Weis J, Spendiff S, Slater CR, Roos A, Lochmüller H. GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice. Hum Mol Genet. 2018; 27(18):3218-3232. DOI 10.1093/hmg/ddy225
• dc.identifier.doi http://dx.doi.org/10.1093/hmg/ddy225
• dc.identifier.issn 0964-6906
• dc.identifier.uri http://hdl.handle.net/10230/42906
• dc.language.iso eng
• dc.publisher Oxford University Press
• dc.relation.ispartof Hum Mol Genet. 2018; 27(18):3218-3232
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305121
• dc.rights © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.title GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion