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Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion

Lookup NU author(s): Dr Lizzie Harris, Dr Rita Barresi, Dr Chiara Marini Bettolo, Dr Ana TopfORCiD, Professor Volker StraubORCiD, Professor Hanns Lochmuller



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2017.

For re-use rights please refer to the publisher's terms and conditions.


Congenital myopathies define a heterogeneous group of neuromuscular diseases with neonatal or childhood hypotonia and muscle weakness. The genetic cause is still unknown in many patients, precluding genetic counselling and better understanding of the physiopathology. To identify novel genetic causes of congenital myopathies, exome sequencing was performed in three consanguineous families. We identified two homozygous frameshift mutations and a homozygous nonsense mutation in the mitogen-activated protein triple kinase ZAK. In total, six affected patients carry these mutations. Reverse transcription polymerase chain reaction and transcriptome analyses suggested nonsense mRNA decay as a main impact of mutations. The patients demonstrated a generalized slowly progressive muscle weakness accompanied by decreased vital capacities. A combination of proximal contractures with distal joint hyperlaxity is a distinct feature in one family. The low endurance and compound muscle action potential amplitude were strongly ameliorated on treatment with anticholinesterase inhibitor in another patient. Common histopathological features encompassed fibre size variation, predominance of type 1 fibre and centralized nuclei. A peculiar subsarcolemmal accumulation of mitochondria pointing towards the centre of the fibre was a novel histological hallmark in one family. These findings will improve the molecular diagnosis of congenital myopathies and implicate the mitogen-activated protein kinase (MAPK) signalling as a novel pathway altered in these rare myopathies.

Publication metadata

Author(s): Vasli N, Harris E, Karamchandani J, Bareke E, Majewski J, Romero NB, Stojkovic T, Barresi R, Tasfaout H, Charlton R, Malfatti E, Bohm J, Marini-Bettolo C, Choquet K, Dicaire MJ, Shao YH, Topf A, O'Ferrall E, Eymard B, Straub V, Blanco G, Lochmuller H, Brais B, Laporte J, Tetreault M

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2017

Volume: 140

Issue: 1

Pages: 37-48

Print publication date: 01/01/2017

Online publication date: 05/11/2016

Acceptance date: 31/08/2016

Date deposited: 08/11/2018

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/aww257


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Funder referenceFunder name
Centre National de la Recherche Scientifique (CNRS)
College de France
Fondation GO
Institut National de la Sante et de la Recherche Medicale (INSERM)
Myotubular Trust
University of Strasbourg
Canadian Institute of Health Research (CIHR)
Fondation maladies rares
Sparks The Children's Medical Research Charity
305121European Union
305444European Union
98482Medical Research Council UK
AFM-15352Association francaise contre les Myopathies
ANR-11-BSV1-026Agence Nationale de la Recherche
G1002274Medical Research Council UK
MDA-113959Muscular Dystrophy Association
MDA-186985Muscular Dystrophy Association
MDA-4075Muscular Dystrophy Association