Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome.
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.
1 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Emily
E
O'Connor
1 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Ana
A
Töpf
2 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Juliane S
JS
Müller
1 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Daniel
D
Cox
1 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Teresinha
T
Evangelista
3 Neuromuscular Unit, Neurology Department, Fundación Sant Joan de Déu, Hospital Materno-Infantil Sant Joan de Déu, Passeig Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain.
Jaume
J
Colomer
4 Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
Angela
A
Abicht
4 Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
Jan
J
Senderek
5 Children's Hospital of Eastern Switzerland, Department of Neuropediatrics, Claudiusstrasse 6, 9006 St. Gallen, Switzerland.
Oswald
O
Hasselmann
6 Paediatric Neurology Unit, Diyarbakır Memorial Hospital, Turkey.
Ahmet
A
Yaramis
1 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Steven H
SH
Laval
1 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK Hanns.Lochmuller@ncl.ac.uk.
Hanns
H
Lochmüller
D000818:Animals; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000503:physiopathology*; D009218:Myosins / Q000235:genetics*; D009469:Neuromuscular Junction / Q000378:metabolism*; D010375:Pedigree; D029961:Zebrafish Proteins
C120896:MYO9A protein, human; D029961:Zebrafish Proteins; C547523:myosin IXa protein, mouse; D009218:Myosins
MYO9A; congenital myasthenic syndrome; neuromuscular junction; unconventional myosin; whole exome sequencing