2. Academic Validation
  3. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect

Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect

  • Am J Hum Genet. 2011 Feb 11;88(2):162-72. doi: 10.1016/j.ajhg.2011.01.008.
Jan Senderek 1,  Juliane S Müller,  Marina Dusl,  Tim M Strom,  Velina Guergueltcheva,  Irmgard Diepolder,  Steven H Laval,  Susan Maxwell,  Judy Cossins,  Sabine Krause,  Nuria Muelas,  Juan J Vilchez,  Jaume Colomer,  Cecilia Jimenez Mallebrera,  Andres Nascimento,  Shahriar Nafissi,  Ariana Kariminejad,  Yalda Nilipour,  Bita Bozorgmehr,  Hossein Najmabadi,  Carmelo Rodolico,  Jörn P Sieb,  Ortrud K Steinlein,  Beate Schlotter,  Benedikt Schoser,  Janbernd Kirschner,  Ralf Herrmann,  Thomas Voit,  Anders Oldfors,  Christopher Lindbergh,  Andoni Urtizberea,  Maja von der Hagen,  Angela Hübner,  Jacqueline Palace,  Kate Bushby,  Volker Straub,  David Beeson,  Angela Abicht,  Hanns Lochmüller
Affiliations

Affiliation

  • 1 Institute of Cell Biology, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland. [email protected]
PMID: 21310273 DOI: 10.1016/j.ajhg.2011.01.008
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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