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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.

SUBMITTER: Senderek J 

PROVIDER: S-EPMC3035713 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect.

Senderek Jan J   Müller Juliane S JS   Dusl Marina M   Strom Tim M TM   Guergueltcheva Velina V   Diepolder Irmgard I   Laval Steven H SH   Maxwell Susan S   Cossins Judy J   Krause Sabine S   Muelas Nuria N   Vilchez Juan J JJ   Colomer Jaume J   Mallebrera Cecilia Jimenez CJ   Nascimento Andres A   Nafissi Shahriar S   Kariminejad Ariana A   Nilipour Yalda Y   Bozorgmehr Bita B   Najmabadi Hossein H   Rodolico Carmelo C   Sieb Jörn P JP   Steinlein Ortrud K OK   Schlotter Beate B   Schoser Benedikt B   Kirschner Janbernd J   Herrmann Ralf R   Voit Thomas T   Oldfors Anders A   Lindbergh Christopher C   Urtizberea Andoni A   von der Hagen Maja M   Hübner Angela A   Palace Jacqueline J   Bushby Kate K   Straub Volker V   Beeson David D   Abicht Angela A   Lochmüller Hanns H  

American journal of human genetics 20110201 2


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  ...[more]

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