@article{1cfac487d9cd4f3fb9cef6fb6039c1ba,
title = "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy",
abstract = "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.920AC change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923CT 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.920AC 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..",
author = "Herrmann, {David N.} and Rita Horvath and Sowden, {Janet E.} and Michael Gonzales and Avencia Sanchez-Mejias and Zhuo Guan and Whittaker, {Roger G.} and Almodovar, {Jorge L.} and Maria Lane and Boglarka Bansagi and Angela Pyle and Veronika Boczonadi and Hanns Lochmuller and Helen Griffin and Chinnery, {Patrick F.} and Lloyd, {Thomas E.} and {Troy Littleton}, J. and Stephan Zuchner",
note = "Funding Information: D.N.H. and J.E.S. are supported by the Inherited Neuropathies Consortium Rare Disease Clinical Research Network, National Institute of Neurological Disorders and Stroke (1U54NS0657); J.T.L. and Z.G. are supported by NIH grant NS40296, the Picower Neurological Disease Research Fund, and The JPB Foundation; T.E.L. is supported by NIH grant NS082563; S.Z., A.S.-M., and M.G. are supported by NIH grants U54NS0657, R01NS075764, R01NS072248, the MDA, and the CMT Association; R.H. is supported by the Medical Research Council (UK) (G1000848) and the European Research Council (309548); R.G.W. is supported by the EPSRC and the Wellcome Trust; B.B. is supported by the Medical Research Council Neuromuscular Translational Research Centre; H.L. receives funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics); and P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK NIHR Senior Investigator and receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease research (G0601943), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The authors would like to thank Eric Logigian for electrophysiological advice and Tracy Forrester for administrative assistance with manuscript preparation. Publisher Copyright: {\textcopyright} 2014 by The American Society of Human Genetics. All rights reserved.",
year = "2014",
doi = "10.1016/j.ajhg.2014.08.007",
language = "English (US)",
volume = "95",
pages = "332--339",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",
}