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.
David N Herrmann  1 ,  Rita Horvath  2 ,  Janet E Sowden  1 ,  Michael Gonzalez ,  Avencia Sanchez-Mejias  3 ,  Zhuo Guan  4 ,  Roger G Whittaker  5 ,  Jorge L Almodovar  6 ,  Maria Lane  2 ,  Boglarka Bansagi  2 ,  Angela Pyle  2 ,  Veronika Boczonadi  2 ,  Hanns Lochmüller  2 ,  Helen Griffin  2 ,  Patrick F Chinnery  2 ,  Thomas E Lloyd  7 ,  J Troy Littleton  4 ,  Stephan Zuchner  8
Affiliations
  • 1. Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 2. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • 3. Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • 4. The Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 5. Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  • 6. Department of Neurology, Dartmouth Hitchcock Clinic, Geisel School of Medicine, Hanover, NH 03755, USA.
  • 7. Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 8. Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: [email protected].
PMID: 25192047 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.