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Ann Neurol. 2017 Mar 2. doi: 10.1002/ana.24905. [Epub ahead of print]

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome.

Author information

1
Department of Molecular Neuroscience, Institute of Neurology, UCL Institute of Neurology, London, WC1N 3BG, UK.
2
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
3
Institute of Human Genetics, Center for Molecular Medicine Cologne and Institute for Genetics University of Cologne, Cologne, 50931, Germany.
4
St George's Hospital, NHS Foundation Trust, London, SW17 0QT, United Kingdom.
5
Human Developmental Genetics, Institute Pasteur, Paris, 75015, France.
6
Department of Cell Biology, Yale School of Medicine, New Haven, CT, 06516, United States.
7
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, WC1N 3BG, UK.
8
Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children NHS foundation trust, London, WC1N 3JH.
9
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva 49202, Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva 49100, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Tel Aviv, Israel.
10
Institute of Child Neurology, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, 49202, Tel Aviv, Israel.
11
Department of Pediatric Neurology, Dubowitz Neuromuscular Center, Great Ormond Street Hospital for Children NHS foundation trust, London, WC1N 3JH, UK.

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 required 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. This article is protected by copyright. All rights reserved.

KEYWORDS:

Congenital myasthenic syndrome; SNARE complex; VAMP1

PMID:
28253535
DOI:
10.1002/ana.24905
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