Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion.
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.
1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404 Illkirch, France.|2 INSERM U974, 67404 Illkirch, France.|3 CNRS, UMR7104, 67404 Illkirch, France.|4 Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France.
Nasim
N
Vasli
5 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Elizabeth
E
Harris
6 Department of Pathology, McGill University Health Centre, Montreal Neurological Institute Hospital, Montreal, QC H3A 2B4, Canada.
Jason
J
Karamchandani
7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.|8 McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada.
Eric
E
Bareke
7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.|8 McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada.
Jacek
J
Majewski
9 Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013 Paris, France.|10 Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Norma B
NB
Romero
10 Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Tanya
T
Stojkovic
5 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Rita
R
Barresi
1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404 Illkirch, France.|2 INSERM U974, 67404 Illkirch, France.|3 CNRS, UMR7104, 67404 Illkirch, France.|4 Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France.
Hichem
H
Tasfaout
5 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Richard
R
Charlton
9 Université Sorbonne, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013 Paris, France.|10 Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Edoardo
E
Malfatti
1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404 Illkirch, France.|2 INSERM U974, 67404 Illkirch, France.|3 CNRS, UMR7104, 67404 Illkirch, France.|4 Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France.
Johann
J
Bohm
5 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Chiara
C
Marini-Bettolo
7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.|11 Rare Neurological Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
Karine
K
Choquet
11 Rare Neurological Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
Marie-Josée
MJ
Dicaire
11 Rare Neurological Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
Yi-Hong
YH
Shao
5 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
Topf
6 Department of Pathology, McGill University Health Centre, Montreal Neurological Institute Hospital, Montreal, QC H3A 2B4, Canada.
Erin
E
O'Ferrall
10 Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Bruno
B
Eymard
5 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Volker
V
Straub
12 Department of Biology, University of York, Wentworth Way, York YO10 5DD, UK.
Gonzalo
G
Blanco
5 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Hanns
H
Lochmüller
7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.|11 Rare Neurological Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
Bernard
B
Brais
1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404 Illkirch, France jocelyn@igbmc.fr martine.tetreault@mail.mcgill.ca.|2 INSERM U974, 67404 Illkirch, France.|3 CNRS, UMR7104, 67404 Illkirch, France.|4 Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France.
Jocelyn
J
Laporte
7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada jocelyn@igbmc.fr martine.tetreault@mail.mcgill.ca.|8 McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada.
Martine
M
Tétreault
D000328:Adult; D003241:Consanguinity; D059472:Exome; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases; D008297:Male; D018656:Muscle Fibers, Fast-Twitch / Q000473:pathology*; D018657:Muscle Fibers, Slow-Twitch / Q000473:pathology*; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*
D011494:Protein Kinases; D020930:MAP Kinase Kinase Kinases; C413047:MAP3K20 protein, human
MLTK; centronuclear myopathy; congenital myopathy; exome; kinase