title: Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome.
abstract: We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lewmice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597-603.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Salpietro
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Weichun
authors.initials: W
authors.lastname: Lin
authors.affiliation: Institute of Human Genetics, Center for Molecular Medicine Cologne, Cologne, Germany.|Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Delle Vedove
authors.affiliation: Institute of Human Genetics, Center for Molecular Medicine Cologne, Cologne, Germany.|Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Storbeck
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Efthymiou
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Andreea
authors.initials: A
authors.lastname: Manole
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Qiaohong
authors.initials: Q
authors.lastname: Ye
authors.affiliation: St George's Hospital, National Health Service Foundation Trust, London, United Kingdom.
authors.forename: Anand
authors.initials: A
authors.lastname: Saggar
authors.affiliation: Human Developmental Genetics, Pasteur Institute, Paris, France.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McElreavey
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT.|Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Krishnakumar
authors.affiliation: Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pitt
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT.|Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Oscar D
authors.initials: OD
authors.lastname: Bello
authors.affiliation: Department of Cell Biology, Yale School of Medicine, New Haven, CT.|Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: Rothman
authors.affiliation: Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.|Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.affiliation: Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.|Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Monika Weisz
authors.initials: MW
authors.lastname: Hubshman
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Institute of Child Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Aharoni
authors.affiliation: Department of Pediatric Neurology, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom.
authors.forename: Adnan Y
authors.initials: AY
authors.lastname: Manzur
authors.affiliation: Institute of Human Genetics, Center for Molecular Medicine Cologne, Cologne, Germany.
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London Institute of Neurology, London, United Kingdom.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000818:Animals; D002675:Child, Preschool; D018389:Codon, Nonsense; D003241:Consanguinity; D004195:Disease Models, Animal; D005260:Female; D006720:Homozygote; D006801:Humans; D007557:Israel; D007730:Kuwait; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000503:physiopathology*; D010375:Pedigree; D050987:Vesicle-Associated Membrane Protein 1 / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D050987:Vesicle-Associated Membrane Protein 1