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 Lochmüller, Helen Griffin, Patrick F. Chinnery, Thomas E. Lloyd, J. Troy Littleton, Stephan L Zuchner

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)332-339
Number of pages8
JournalAmerican Journal of Human Genetics
Volume95
Issue number3
DOIs
StatePublished - Jan 1 2014

Fingerprint

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; Lochmüller, Hanns; Griffin, Helen; Chinnery, Patrick F.; Lloyd, Thomas E.; Littleton, J. Troy; Zuchner, Stephan L.

In: American Journal of Human Genetics, Vol. 95, No. 3, 01.01.2014, 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, Lochmüller, H, Griffin, H, Chinnery, PF, Lloyd, TE, Littleton, JT & Zuchner, SL 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 ; Lochmüller, Hanns ; Griffin, Helen ; Chinnery, Patrick F. ; Lloyd, Thomas E. ; Littleton, J. Troy ; Zuchner, Stephan L. / 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.
@article{d22446e025854d2ebde50d67e7432310,
title = "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.",
author = "Herrmann, {David N.} and Rita Horvath and Sowden, {Janet E.} and Michael Gonzales and Avencia Sanchez-Mejias and Zhuo Guan and Whittaker, {Roger G.} and Almodovar, {Jorge L.} and Maria Lane and Boglarka Bansagi and Angela Pyle and Veronika Boczonadi and Hanns Lochm{\"u}ller and Helen Griffin and Chinnery, {Patrick F.} and Lloyd, {Thomas E.} and Littleton, {J. Troy} and Zuchner, {Stephan L}",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.ajhg.2014.08.007",
language = "English",
volume = "95",
pages = "332--339",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy.

AU - Herrmann, David N.

AU - Horvath, Rita

AU - Sowden, Janet E.

AU - Gonzales, Michael

AU - Sanchez-Mejias, Avencia

AU - Guan, Zhuo

AU - Whittaker, Roger G.

AU - Almodovar, Jorge L.

AU - Lane, Maria

AU - Bansagi, Boglarka

AU - Pyle, Angela

AU - Boczonadi, Veronika

AU - Lochmüller, Hanns

AU - Griffin, Helen

AU - Chinnery, Patrick F.

AU - Lloyd, Thomas E.

AU - Littleton, J. Troy

AU - Zuchner, Stephan L

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84908236633&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908236633&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.08.007

DO - 10.1016/j.ajhg.2014.08.007

M3 - Article

C2 - 25192047

AN - SCOPUS:84908236633

VL - 95

SP - 332

EP - 339

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -