Document Detail

Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy.
MedLine Citation:
PMID:  25192047     Owner:  NLM     Status:  In-Data-Review    
Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies.
David N Herrmann; Rita Horvath; Janet E Sowden; Michael Gonzales; Avencia Sanchez-Mejias; Zhuo Guan; Roger G Whittaker; Jorge L Almodovar; Maria Lane; Boglarka Bansagi; Angela Pyle; Veronika Boczonadi; Hanns Lochmüller; Helen Griffin; Patrick F Chinnery; Thomas E Lloyd; J Troy Littleton; Stephan Zuchner
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  American journal of human genetics     Volume:  95     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-09-06     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  332-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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