PUBLICATION
Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect
- Authors
- Senderek, J., Müller, J.S., Dusl, M., Strom, T.M., Guergueltcheva, V., Diepolder, I., Laval, S.H., Maxwell, S., Cossins, J., Krause, S., Muelas, N., Vilchez, J.J., Colomer, J., Mallebrera, C.J., Nascimento, A., Nafissi, S., Kariminejad, A., Nilipour, Y., Bozorgmehr, B., Najmabadi, H., Rodolico, C., Sieb, J.P., Steinlein, O.K., 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.
- ID
- ZDB-PUB-110214-35
- Date
- 2011
- Source
- American journal of human genetics 88(2): 162-172 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Humans
- Fluorescent Antibody Technique
- Hexosamines/metabolism*
- Synaptic Transmission/physiology
- Male
- Animals
- Cells, Cultured
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Mutation/genetics*
- In Situ Hybridization, Fluorescence
- Gene Expression Regulation, Developmental
- Zebrafish
- Case-Control Studies
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/metabolism
- Glycosylation
- Blotting, Western
- Myasthenic Syndromes, Congenital/genetics*
- Myasthenic Syndromes, Congenital/pathology
- Neuromuscular Junction/physiology
- Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/genetics*
- Pedigree
- Immunoenzyme Techniques
- RNA, Messenger/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Female
- Signal Transduction*
- Genetic Linkage
- PubMed
- 21310273 Full text @ Am. J. Hum. Genet.
Citation
Senderek, J., Müller, J.S., Dusl, M., Strom, T.M., Guergueltcheva, V., Diepolder, I., Laval, S.H., Maxwell, S., Cossins, J., Krause, S., Muelas, N., Vilchez, J.J., Colomer, J., Mallebrera, C.J., Nascimento, A., Nafissi, S., Kariminejad, A., Nilipour, Y., Bozorgmehr, B., Najmabadi, H., Rodolico, C., Sieb, J.P., Steinlein, O.K., 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. American journal of human genetics. 88(2):162-172.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping