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Lookup NU author(s): Emily O'Connor, Dr Ana TopfORCiD, Dr Juliane Mueller, Daniel CoxORCiD, Dr Teresinha Evangelista, Dr Steven Laval, Professor Hanns Lochmuller
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Congenital myasthenic syndromes result from defects in the neuromuscular junction. Using whole exome sequencing, O'Connor et al. identify mutations in a novel candidate gene, MYO9A, which encodes an unconventional myosin. They provide preliminary evidence that MYO9A contributes to formation of the neuromuscular junction via effects on the presynaptic motor axon.Congenital myasthenic syndromes result from defects in the neuromuscular junction. Using whole exome sequencing, O'Connor et al. identify mutations in a novel candidate gene, MYO9A, which encodes an unconventional myosin. They provide preliminary evidence that MYO9A contributes to formation of the neuromuscular junction via effects on the presynaptic motor axon.Congenital myasthenic syndromes are a group of rare and genetically heterogenous disorders resulting from defects in the structure and function of the neuromuscular junction. Patients with congenital myasthenic syndrome exhibit fatigable muscle weakness with a variety of accompanying phenotypes depending on the protein affected. A cohort of patients with a clinical diagnosis of congenital myasthenic syndrome that lacked a genetic diagnosis underwent whole exome sequencing in order to identify genetic causation. Missense biallelic mutations in the MYO9A gene, encoding an unconventional myosin, were identified in two unrelated families. Depletion of MYO9A in NSC-34 cells revealed a direct effect of MYO9A on neuronal branching and axon guidance. Morpholino-mediated knockdown of the two MYO9A orthologues in zebrafish, myo9aa/ab, demonstrated a requirement for MYO9A in the formation of the neuromuscular junction during development. The morphants displayed shortened and abnormally branched motor axons, lack of movement within the chorion and abnormal swimming in response to tactile stimulation. We therefore conclude that MYO9A deficiency may affect the presynaptic motor axon, manifesting in congenital myasthenic syndrome. These results highlight the involvement of unconventional myosins in motor axon functionality, as well as the need to look outside traditional neuromuscular junction-specific proteins for further congenital myasthenic syndrome candidate genes.
Author(s): O'Connor E, Topf A, Muller JS, Cox D, Evangelista T, Colomer J, Abicht A, Senderek J, Hasselmann O, Yaramis A, Laval SH, Lochmuller H
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2016
Volume: 139
Issue: 8
Pages: 2143-2153
Print publication date: 01/08/2016
Online publication date: 03/06/2016
Acceptance date: 20/04/2016
Date deposited: 09/11/2016
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/brain/aww130
DOI: 10.1093/brain/aww130
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