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

• Published in: American journal of human genetics 2014-09, Vol.95 (3), p.332-339
• Main Authors: Herrmann, David N., Horvath, Rita, Sowden, Janet E., Gonzales, Michael, Sanchez-Mejias, Avencia, Guan, Zhuo, Whittaker, Roger G., Almodovar, Jorge L., Lane, Maria, Bansagi, Boglarka, Pyle, Angela, Boczonadi, Veronika, Lochmüller, Hanns, Griffin, Helen, Chinnery, Patrick F., Lloyd, Thomas E., Littleton, J. Troy, Zuchner, Stephan
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Animals; Autoimmune diseases; Child; Drosophila - genetics; Drosophila - growth & development; Drosophila - metabolism; Electrophysiology; Exocytosis - physiology; Female; Genes, Dominant - genetics; Humans; Insects; Lambert-Eaton Myasthenic Syndrome - genetics; Male; Middle Aged; Motor ability; Motor Neuron Disease - genetics; Mutation; Mutation - genetics; Nervous system; Neurons; Pedigree; Peripheral Nervous System Diseases - genetics; Synaptic Transmission; Synaptotagmin II - genetics; Young Adult
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2014.08.007

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.