title: Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect.
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.
authors.affiliation: Institute of Cell Biology, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland. jan.senderek@cell.biol.ethz.ch
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Müller
authors.forename: Marina
authors.initials: M
authors.lastname: Dusl
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.forename: Irmgard
authors.initials: I
authors.lastname: Diepolder
authors.forename: Steven H
authors.initials: SH
authors.lastname: Laval
authors.forename: Susan
authors.initials: S
authors.lastname: Maxwell
authors.forename: Judy
authors.initials: J
authors.lastname: Cossins
authors.forename: Sabine
authors.initials: S
authors.lastname: Krause
authors.forename: Nuria
authors.initials: N
authors.lastname: Muelas
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Vilchez
authors.forename: Jaume
authors.initials: J
authors.lastname: Colomer
authors.forename: Cecilia Jimenez
authors.initials: CJ
authors.lastname: Mallebrera
authors.forename: Andres
authors.initials: A
authors.lastname: Nascimento
authors.forename: Shahriar
authors.initials: S
authors.lastname: Nafissi
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.forename: Yalda
authors.initials: Y
authors.lastname: Nilipour
authors.forename: Bita
authors.initials: B
authors.lastname: Bozorgmehr
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.forename: Jörn P
authors.initials: JP
authors.lastname: Sieb
authors.forename: Ortrud K
authors.initials: OK
authors.lastname: Steinlein
authors.forename: Beate
authors.initials: B
authors.lastname: Schlotter
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Ralf
authors.initials: R
authors.lastname: Herrmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
authors.forename: Christopher
authors.initials: C
authors.lastname: Lindbergh
authors.forename: Andoni
authors.initials: A
authors.lastname: Urtizberea
authors.forename: Maja
authors.initials: M
authors.lastname: von der Hagen
authors.forename: Angela
authors.initials: A
authors.lastname: Hübner
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Palace
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: David
authors.initials: D
authors.lastname: Beeson
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D008040:Genetic Linkage; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics*; D006031:Glycosylation; D006595:Hexosamines / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000473:pathology; D009469:Neuromuscular Junction / Q000502:physiology; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D009435:Synaptic Transmission / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D006595:Hexosamines; D012333:RNA, Messenger; D029961:Zebrafish Proteins; C497511:GFPT1 protein, human; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)