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

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.

• Authors: David N Herrmann, Rita Horvath, Janet E Sowden, Michael Gonzalez, Michael Gonzales, Avencia Sanchez-Mejias, Zhuo Guan, Roger G Whittaker, Jorge L Almodovar, Maria Lane, Boglarka Bansagi, Angela Pyle, Veronika Boczonadi, Hanns Lochmüller, Helen Griffin, Patrick F Chinnery, Thomas E Lloyd, J Troy Littleton, Stephan Zuchner
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 95 Issue 3 Pg. 332-9 (Sep 04 2014) ISSN: 1537-6605 [Electronic] United States
• PMID: 25192047 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• SYT2 protein, human
• Synaptotagmin II

Topics

• Adolescent
• Adult
• Aged
• Animals
• Child
• Drosophila (genetics, growth & development, 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