Toggle Main Menu Toggle Search

ePrints

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

Lookup NU author(s): Professor Rita Horvath, Dr Roger Whittaker, Dr Boglarka Bansagi, Dr Angela Pyle, Dr Veronika Boczonadi, Professor Hanns Lochmuller, Dr Helen Griffin, Professor Patrick Chinnery

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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.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

URL: http://dx.doi.org/10.1016/j.ajhg.2014.08.007

DOI: 10.1016/j.ajhg.2014.08.007


Altmetrics

Altmetrics provided by Altmetric


Actions

    Link to this publication


Share