Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy
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 Synaptota...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier B.V.
2017
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| Online Access: | http://hdl.handle.net/1721.1/106814 https://orcid.org/0000-0001-5576-2887 |
| _version_ | 1811074945518665728 |
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| author | Herrmann, David N. Horvath, Rita Sowden, Janet E. Gonzales, Michael Sanchez-Mejias, Avencia Whittaker, Roger G. Almodovar, Jorge L. Lane, Maria Bansagi, Boglarka Pyle, Angela Boczonadi, Veronika Lochmüller, Hanns Griffin, Helen Chinnery, Patrick F. Lloyd, Thomas E. Zuchner, Stephan Guan, Zhuo Littleton, J. Troy |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Herrmann, David N. Horvath, Rita Sowden, Janet E. Gonzales, Michael Sanchez-Mejias, Avencia Whittaker, Roger G. Almodovar, Jorge L. Lane, Maria Bansagi, Boglarka Pyle, Angela Boczonadi, Veronika Lochmüller, Hanns Griffin, Helen Chinnery, Patrick F. Lloyd, Thomas E. Zuchner, Stephan Guan, Zhuo Littleton, J. Troy |
| author_sort | Herrmann, David N. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:57:56Z |
| format | Article |
| id | mit-1721.1/106814 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:57:56Z |
| publishDate | 2017 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/1068142022-09-30T18:01:02Z 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 Whittaker, Roger G. Almodovar, Jorge L. Lane, Maria Bansagi, Boglarka Pyle, Angela Boczonadi, Veronika Lochmüller, Hanns Griffin, Helen Chinnery, Patrick F. Lloyd, Thomas E. Zuchner, Stephan Guan, Zhuo Littleton, J. Troy Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Picower Institute for Learning and Memory Littleton, J. Troy Guan, Zhuo Littleton, J. Troy 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. National Institutes of Health (U.S.) (NIH Grant NS40296) Picower Institute for Learning and Memory (Picower Neurological Disease Research Fund) JPB Foundation 2017-01-31T18:46:51Z 2017-01-31T18:46:51Z 2014-09 2014-07 Article http://purl.org/eprint/type/JournalArticle 00029297 http://hdl.handle.net/1721.1/106814 Herrmann, David N., Rita Horvath, Janet E. Sowden, Michael Gonzales, Avencia Sanchez-Mejias, Zhuo Guan, Roger G. Whittaker, et al. “Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy.” American Journal of Human Genetics 95, no. 3 (September 2014): 332–339. https://orcid.org/0000-0001-5576-2887 en_US http://dx.doi.org/10.1016/j.ajhg.2014.08.007 American Journal of Human Genetics Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier B.V. Prof. Littleton |
| spellingShingle | Herrmann, David N. Horvath, Rita Sowden, Janet E. Gonzales, Michael Sanchez-Mejias, Avencia Whittaker, Roger G. Almodovar, Jorge L. Lane, Maria Bansagi, Boglarka Pyle, Angela Boczonadi, Veronika Lochmüller, Hanns Griffin, Helen Chinnery, Patrick F. Lloyd, Thomas E. Zuchner, Stephan Guan, Zhuo Littleton, J. Troy Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy |
| title | Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy |
| title_full | Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy |
| title_fullStr | Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy |
| title_full_unstemmed | Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy |
| title_short | Synaptotagmin 2 Mutations Cause an Autosomal-Dominant Form of Lambert-Eaton Myasthenic Syndrome and Nonprogressive Motor Neuropathy |
| title_sort | synaptotagmin 2 mutations cause an autosomal dominant form of lambert eaton myasthenic syndrome and nonprogressive motor neuropathy |
| url | http://hdl.handle.net/1721.1/106814 https://orcid.org/0000-0001-5576-2887 |
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