Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy

David N. Herrmann, Rita Horvath, Janet E. Sowden, Michael Gonzales, Avencia Sanchez-Mejias, Zhuo Guan, Roger G. Whittaker, Jorge L. Almodovar, Maria Lane, Boglarka Bansagi, Angela Pyle, Veronika Boczonadi, Hanns Lochmuller, Helen Griffin, Patrick F. Chinnery, Thomas E. Lloyd, J. Troy Littleton, Stephan Zuchner

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63 Scopus citations

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 presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies.

Original languageEnglish (US)
Pages (from-to)332-339
Number of pages8
JournalAmerican journal of human genetics
Volume95
Issue number3
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Herrmann, D. N., Horvath, R., Sowden, J. E., Gonzales, M., Sanchez-Mejias, A., Guan, Z., Whittaker, R. G., Almodovar, J. L., Lane, M., Bansagi, B., Pyle, A., Boczonadi, V., Lochmuller, H., Griffin, H., Chinnery, P. F., Lloyd, T. E., Troy Littleton, J., & Zuchner, S. (2014). Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. American journal of human genetics, 95(3), 332-339. https://doi.org/10.1016/j.ajhg.2014.08.007