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Homozygous mutations in VAMP 1 cause a presynaptic congenital myasthenic syndrome
Author(s) -
Salpietro Vincenzo,
Lin Weichun,
Delle Vedove Andrea,
Storbeck Markus,
Liu Yun,
Efthymiou Stephanie,
Manole Andreea,
Wiethoff Sarah,
Ye Qiaohong,
Saggar Anand,
McElreavey Kenneth,
Krishnakumar Shyam S.,
Pitt Matthew,
Bello Oscar D.,
Rothman James E.,
BaselVanagaite Lina,
Hubshman Monika Weisz,
Aharoni Sharon,
Manzur Adnan Y.,
Wirth Brunhilde,
Houlden Henry
Publication year - 2017
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24905
Subject(s) - congenital myasthenic syndrome , neuromuscular junction , exome sequencing , nonsense mutation , neuromuscular transmission , medicine , mutation , neuroscience , myasthenia gravis , genetics , biology , gene , missense mutation
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_64delAGGTTCCCC 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 VAMP1 lew/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