Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 95, Issue 3, Pages 332-339Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2014.08.007
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Funding
- Inherited Neuropathies Consortium Rare Disease Clinical Research Network, National Institute of Neurological Disorders and Stroke [1U54NS0657]
- NIH [NS40296, NS082563, U54NS0657, R01NS075764, R01NS072248]
- Picower Neurological Disease Research Fund
- JPB Foundation
- MDA
- CMT Association
- Medical Research Council (UK) [G1000848]
- European Research Council [309548]
- EPSRC
- Wellcome Trust
- Medical Research Council Neuromuscular Translational Research Centre
- European Union [305444, 305121]
- Wellcome Trust Centre for Mitochondrial Research [096919Z/11/Z]
- Medical Research Council (UK) Centre for Translational Muscle Disease research [G0601943]
- EU FP7 TIRCON
- National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
- Newcastle University
- Medical Research Council [G1000848, MR/K000608/1, G1002274, G0601943] Funding Source: researchfish
- MRC [MR/K000608/1, G1002274, G1000848, G0601943] Funding Source: UKRI
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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.
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