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 language | English (US) |
|---|---|
| Pages (from-to) | 332-339 |
| Number of pages | 8 |
| Journal | American Journal of Human Genetics |
| Volume | 95 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
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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 journal › Article
}
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 - Lochmuller, Hanns
AU - Griffin, Helen
AU - Chinnery, Patrick F.
AU - Lloyd, Thomas
AU - Troy Littleton, J.
AU - Zuchner, Stephan
PY - 2014
Y1 - 2014
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.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..
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.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..
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
VL - 95
SP - 332
EP - 339
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -