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Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect

Authors:	Senderek Jan Müller Juliane S Dusl Marina Strom Tim M Guergueltcheva Velina Diepolder Irmgard Laval Steven H Maxwell Susan Cossins Judy Krause Sabine Muelas Nuria Vilchez Juan J Colomer Jaume Mallebrera Cecilia Jimenez Nascimento Andres Nafissi Shahriar Kariminejad Ariana Nilipour Yalda Bozorgmehr Bita Najmabadi Hossein Rodolico Carmelo Sieb Jörn P Steinlein Ortrud K Schlotter Beate Schoser Benedikt Kirschner Janbernd Herrmann Ralf Voit Thomas Oldfors Anders Lindbergh Christopher Urtizberea Andoni von der Hagen Maja Hübner Angela Palace Jacqueline Bushby Kate Straub Volker Beeson David

Institution:	¹Institute of Cell Biology, Eidgenössische Technische Hochschule (ETH) Zürich, 8093 Zürich, Switzerland;²Institute of Human Genetics, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, 52074 Aachen, Germany;³Institute of Human Genetics, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK;⁴Friedrich-Baur-Institut, Department of Neurology, Ludwig Maximilians University, 80336 Munich, Germany;⁵Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany;⁶Clinic of Neurology, University Hospital Alexandrovska, 1431 Sofia, Bulgaria;⁷Neurosciences Group, Weatherall Institute of Molecular Medicine, Department of Clinical Neurology, University of Oxford OX3 9DU, UK;⁸Servicio de Neurologia, Hospital La Fe and Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Neurodegenerativas (CIBERNED), 46009 Valencia, Spain;⁹Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Deu, 08950 Esplugues (Barcelona), Spain;¹⁰Department of Neurology, Tehran University of Medical Sciences, 14155 Tehran, Iran;¹¹Kariminejad-Najmabadi Pathology and Genetics Center, 14667 Tehran, Iran;¹²Neuropathology Laboratory, Toos Hospital, 15969 Tehran, Iran;¹³Departments of Neurosciences, Psychiatry and Anaesthesiology, Azienda Ospedaliera Universitaria (A.O.U.) “G. Martino”, 98125 Messina, Italy;¹⁴Department of Neurology, Geriatric Medicine and Palliative Care, Hanse-Klinikum, 18435 Stralsund, Germany;¹⁵Institute of Human Genetics, Ludwig Maximilians University, 80336 Munich, Germany;¹⁶Division of Neuropaediatrics and Muscle Disorders, University Medical Center, 79106 Freiburg, Germany;¹⁷Department of Paediatrics I, University Hospital Essen, 45122 Essen, Germany;¹⁸Université Pierre et Marie Curie (UPMC) - Association Institut de Myologie (AIM) Unité Mixte de Recherche (UMR) S974, Institut National de la Santé et de la Recherche Médicale (INSERM) U 974, Centre National de la Recherche Scientifique (CNRS) UMR 7215, Institut de Myologie, Université Pierre et Marie Curie - Paris 6, 75013 Paris, France;¹⁹Department of Pathology, Institute of Biomedicine, University of Gothenburg, 405 30 Gothenburg, Sweden;²⁰Neuromuscular Center, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden;²¹Hôpital Marin, 64701 Hendaye, France;²²University Children's Hospital, Technical University Dresden, 01307 Dresden, Germany;²³Congenital Myasthenic Syndrome National Commissioning Group (CMS NCG), Department of Clinical Neurology, John Radcliffe Hospital, Oxford OX3 9DU, UK

Abstract:	Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromuscular transmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6-phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general.

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