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PMID:21310273

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Citation

Senderek, J, Müller, JS, Dusl, M, Strom, TM, Guergueltcheva, V, Diepolder, I, Laval, SH, Maxwell, S, Cossins, J, Krause, S, Muelas, N, Vilchez, JJ, Colomer, J, Mallebrera, CJ, Nascimento, A, Nafissi, S, Kariminejad, A, Nilipour, Y, Bozorgmehr, B, Najmabadi, H, Rodolico, C, Sieb, JP, Steinlein, OK, Schlotter, B, Schoser, B, Kirschner, J, Herrmann, R, Voit, T, Oldfors, A, Lindbergh, C, Urtizberea, A, von der Hagen, M, Hübner, A, Palace, J, Bushby, K, Straub, V, Beeson, D, Abicht, A and Lochmüller, H (2011) Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am. J. Hum. Genet. 88:162-72

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.

Links

PubMed PMC3035713 Online version:10.1016/j.ajhg.2011.01.008

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:Q3S344

involved_in

GO:0007528: neuromuscular junction development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110222-1

P

Seeded From UniProt

complete

DANRE:Q3S344

involved_in

GO:0007519: skeletal muscle tissue development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110222-1

P

Seeded From UniProt

complete

DANRE:X1WGR7

involved_in

GO:0007528: neuromuscular junction development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110222-1

P

Seeded From UniProt

complete

DANRE:X1WGR7

involved_in

GO:0007519: skeletal muscle tissue development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-110222-1

P

Seeded From UniProt

complete


See also

References

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