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 Lloyd, J. Troy Littleton, Stephan Zuchner

Research output: Contribution to journalArticle

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.920AC change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923CT 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.920AC 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
Externally publishedYes

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Synaptotagmin II
Lambert-Eaton Myasthenic Syndrome
Mutation
Synaptic Vesicles
Neuromuscular Junction Diseases
Congenital Myasthenic Syndromes
Synaptotagmins
Exome
Calcium
Neuromuscular Junction
Exocytosis
Motor Neurons
Missense Mutation
Peripheral Nerves
Aspartic Acid
Synaptic Transmission
Drosophila
Neurotransmitter Agents
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. / 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; Lochmuller, Hanns; Griffin, Helen; Chinnery, Patrick F.; Lloyd, Thomas; Troy Littleton, J.; Zuchner, Stephan.

In: American Journal of Human Genetics, Vol. 95, No. 3, 2014, p. 332-339.

Research output: Contribution to journalArticle

Herrmann, DN, Horvath, R, Sowden, JE, Gonzales, M, Sanchez-Mejias, A, Guan, Z, Whittaker, RG, Almodovar, JL, Lane, M, Bansagi, B, Pyle, A, Boczonadi, V, Lochmuller, H, Griffin, H, Chinnery, PF, Lloyd, T, 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, vol. 95, no. 3, pp. 332-339. https://doi.org/10.1016/j.ajhg.2014.08.007
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 ; Lochmuller, Hanns ; Griffin, Helen ; Chinnery, Patrick F. ; Lloyd, Thomas ; Troy Littleton, J. ; Zuchner, Stephan. / Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 3. pp. 332-339.
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