Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

Ann Neurol. 2017 Apr;81(4):597-603. doi: 10.1002/ana.24905.

Vincenzo Salpietro ¹, Weichun Lin ², Andrea Delle Vedove ³ ⁴, Markus Storbeck ³ ⁴, Yun Liu ², Stephanie Efthymiou ¹, Andreea Manole ¹, Sarah Wiethoff ¹, Qiaohong Ye ², Anand Saggar ⁵, Kenneth McElreavey ⁶, Shyam S Krishnakumar ⁷ ⁸, SYNAPS Study Group, Matthew Pitt ⁹, Oscar D Bello ⁷ ⁸, James E Rothman ⁷ ⁸, Lina Basel-Vanagaite ¹⁰ ¹¹ ¹², Monika Weisz Hubshman ¹⁰ ¹¹ ¹², Sharon Aharoni ¹² ¹³, Adnan Y Manzur ¹⁴, Brunhilde Wirth ³, Henry Houlden ¹

Affiliations

1 Department of Molecular Neuroscience, Institute of Neurology, University College London Institute of Neurology, London, United Kingdom.
2 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX.
3 Institute of Human Genetics, Center for Molecular Medicine Cologne, Cologne, Germany.
4 Institute for Genetics, University of Cologne, Cologne, Germany.
5 St George's Hospital, National Health Service Foundation Trust, London, United Kingdom.
6 Human Developmental Genetics, Pasteur Institute, Paris, France.
7 Department of Cell Biology, Yale School of Medicine, New Haven, CT.
8 Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, London, United Kingdom.
9 Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, United Kingdom.
10 Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
11 Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.
12 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
13 Institute of Child Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
14 Department of Pediatric Neurology, Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom.

PMID: 28253535 DOI: 10.1002/ana.24905

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 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.

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