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Lookup NU author(s): Professor Rita HorvathORCiD, Professor Roger Whittaker, Dr Boglarka Bansagi, Dr Angela Pyle, Dr Veronika Boczonadi, Professor Hanns Lochmuller, Dr Helen GriffinORCiD, Professor Patrick Chinnery
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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 presynap tic congenital myasthenic syndromes and link them with hereditary motor axonopathies.
Author(s): Herrmann DN, Horvath R, Sowden JE, Gonzales M, Sanchez-Mejias A, Guan Z, Whittaker RG, Almodovar JL, Lane M, Bansagi B, Pyle A, Boczonadi V, Lochmuller H, Griffin H, Chinnery PE, Lloyd TE, Littleton JT, Zuchner S
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2014
Volume: 95
Issue: 3
Pages: 332-339
Print publication date: 04/09/2014
Online publication date: 04/09/2014
Acceptance date: 15/08/2014
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: http://dx.doi.org/10.1016/j.ajhg.2014.08.007
DOI: 10.1016/j.ajhg.2014.08.007
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