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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.

Original publication

DOI

10.1016/j.ajhg.2011.01.008

Type

Journal article

Journal

Am J Hum Genet

Publication Date

11/02/2011

Volume

88

Pages

162 - 172

Keywords

Animals, Blotting, Western, Case-Control Studies, Cells, Cultured, Embryo, Nonmammalian, Female, Fluorescent Antibody Technique, Gene Expression Regulation, Developmental, Genetic Linkage, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Glycosylation, Hexosamines, Humans, Immunoenzyme Techniques, In Situ Hybridization, Fluorescence, Male, Mutation, Myasthenic Syndromes, Congenital, Neuromuscular Junction, Pedigree, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Synaptic Transmission, Zebrafish, Zebrafish Proteins