Hexosamine Biosynthetic Pathway Mutations Cause Neuromuscular Transmission Defect

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• 作者：Jan Senderek¹ ; ² ; ²⁴ ; ^{jan.senderek@cell.biol.ethz.ch} ; Juliane S. Mü ; ller³ ; ²⁴ ; Marina Dusl⁴ ; Tim M. Strom⁵ ; Velina Guergueltcheva⁶ ; Irmgard Diepolder² ; Steven H. Laval³ ; Susan Maxwell⁷ ; Judy Cossins⁷ ; Sabine Krause⁴ ; Nuria Muelas⁸ ; Juan J. Vilchez⁸ ; Jaume Colomer⁹ ; Cecilia Jimenez Mallebrera⁹ ; Andres Nascimento⁹ ; Shahriar Nafissi¹⁰ ; Ariana Kariminejad¹¹ ; Yalda Nilipour¹² ; Bita Bozorgmehr¹¹ ; Hossein Najmabadi¹¹ ; Carmelo Rodolico¹³ ; Jö ; rn P. Sieb¹⁴ ; Ortrud K. Steinlein¹⁵ ; Beate Schlotter⁴ ; Benedikt Schoser⁴ ; Janbernd Kirschner¹⁶ ; Ralf Herrmann¹⁷ ; Thomas Voit¹⁸ ; Anders Oldfors¹⁹ ; Christopher Lindbergh²⁰ ; Andoni Urtizberea²¹ ; Maja von der Hagen²² ; Angela Hü ; bner²² ; Jacqueline Palace²³ ; Kate Bushby³ ; Volker Straub³ ; David Beeson⁷ ; Angela Abicht⁴ ; Hanns Lochmü ; ller³ ; ^{hanns.lochmuller@ncl.ac.uk}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 February 2011
• 年：2011
• 卷：88
• 期：2
• 页码：162-172
• 全文大小：1015 K

文摘

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.