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

Am J Hum Genet. 2014 Sep 4;95(3):332-9. doi: 10.1016/j.ajhg.2014.08.007.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Child
  • Drosophila / genetics
  • Drosophila / growth & development
  • Drosophila / metabolism
  • Electrophysiology
  • Exocytosis / physiology
  • Female
  • Genes, Dominant / genetics*
  • Humans
  • Lambert-Eaton Myasthenic Syndrome / genetics*
  • Male
  • Middle Aged
  • Motor Neuron Disease / genetics*
  • Mutation / genetics*
  • Pedigree
  • Peripheral Nervous System Diseases / genetics*
  • Synaptic Transmission
  • Synaptotagmin II / genetics*
  • Young Adult

Substances

  • SYT2 protein, human
  • Synaptotagmin II