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.
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Herrmann
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Sowden
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzales
authors.affiliation: Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Avencia
authors.initials: A
authors.lastname: Sanchez-Mejias
authors.affiliation: The Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Whittaker
authors.affiliation: Department of Neurology, Dartmouth Hitchcock Clinic, Geisel School of Medicine, Hanover, NH 03755, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Almodovar
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Lane
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Bansagi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Veronika
authors.initials: V
authors.lastname: Boczonadi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lloyd
authors.affiliation: The Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: J Troy
authors.initials: JT
authors.lastname: Littleton
authors.affiliation: Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: szuchner@med.miami.edu.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D004594:Electrophysiology; D005089:Exocytosis / Q000502:physiology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D009435:Synaptic Transmission; D050861:Synaptotagmin II / Q000235:genetics*; D055815:Young Adult
chemical_list: C494262:SYT2 protein, human; D050861:Synaptotagmin II