Hexosamine Biosynthetic Pathway Mutations Cause Neuromuscular Transmission Defect

• Published in: American journal of human genetics 2011-02, Vol.88 (2), p.162-172
• Main 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, Abicht, Angela, Lochmüller, Hanns
• Format: Article
• Language: English
• Subjects: Animals; Basic Medicine; Biological and medical sciences; Blotting, Western; Case-Control Studies; Cells, Cultured; Danio rerio; Embryo, Nonmammalian - cytology; Embryo, Nonmammalian - metabolism; Embryos; Female; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; General aspects. Genetic counseling; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) - genetics; Glycosylation; Hexosamines - metabolism; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Male; Medical genetics; Medical sciences; Medicinska grundvetenskaper; Molecular and cellular biology; Musculoskeletal system; Mutation; Mutation - genetics; Myasthenic Syndromes, Congenital - genetics; Myasthenic Syndromes, Congenital - pathology; Neuromuscular Junction - physiology; Neurons; Pedigree; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Synaptic Transmission - physiology; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.01.008

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.