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/lew mice, 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: Vincenzo Salpietro, Weichun Lin, Andrea Delle Vedove, Markus Storbeck, Yun Liu, Stephanie Efthymiou, Andreea Manole, Sarah Wiethoff, Qiaohong Ye, Anand Saggar, Kenneth McElreavey, Shyam S Krishnakumar, SYNAPS Study Group, Matthew Pitt, Oscar D Bello, James E Rothman, Lina Basel-Vanagaite, Monika Weisz Hubshman, Sharon Aharoni, Adnan Y Manzur, Brunhilde Wirth, Henry Houlden
• Journal: Annals of neurology (Ann Neurol) Vol. 81 Issue 4 Pg. 597-603 (04 2017) ISSN: 1531-8249 [Electronic] United States
• PMID: 28253535 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Annals of Neurology Published by Wiley Periodicals, Inc.

Chemical References

• Codon, Nonsense
• Vesicle-Associated Membrane Protein 1

Topics

• Animals
• Child, Preschool
• Codon, Nonsense
• Consanguinity
• Disease Models, Animal
• Female
• Homozygote
• Humans
• Israel
• Kuwait
• Male
• Mice
• Mice, Transgenic
• Myasthenic Syndromes, Congenital (genetics, physiopathology)
• Neuromuscular Junction (physiopathology)
• Pedigree
• Vesicle-Associated Membrane Protein 1 (genetics)