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Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy

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.

Publication metadata

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


DOI: 10.1016/j.ajhg.2014.08.007


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Funder referenceFunder name
Medical Research Council Neuromuscular Translational Research Centre
National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle University
Picower Neurological Disease Research Fund
CMT Association
JPB Foundation
Wellcome Trust
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research
305121European Union
305444European Union
1U54NS0657Inherited Neuropathies Consortium Rare Disease Clinical Research Network, National Institute of Neurological Disorders and Stroke
309548European Research Council
G1000848Medical Research Council (UK)
G0601943Medical Research Council (UK) Centre for Translational Muscle Disease research