2. Academic Validation
  3. Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion

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

  • Brain. 2017 Jan;140(1):37-48. doi: 10.1093/brain/aww257.
Nasim Vasli 1 2 3 4,  Elizabeth Harris 5,  Jason Karamchandani 6,  Eric Bareke 7 8,  Jacek Majewski 7 8,  Norma B Romero 9 10,  Tanya Stojkovic 10,  Rita Barresi 5,  Hichem Tasfaout 1 2 3 4,  Richard Charlton 5,  Edoardo Malfatti 9 10,  Johann Bohm 1 2 3 4,  Chiara Marini-Bettolo 5,  Karine Choquet 7 11,  Marie-Josée Dicaire 11,  Yi-Hong Shao 11,  Ana Topf 5,  Erin O'Ferrall 6,  Bruno Eymard 10,  Volker Straub 5,  Gonzalo Blanco 12,  Hanns Lochmüller 5,  Bernard Brais 7 11,  Jocelyn Laporte 13 2 3 4,  Martine Tétreault 14 8
Affiliations

Affiliations

  • 1 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404 Illkirch, France.
  • 2 2 INSERM U974, 67404 Illkirch, France.
  • 3 3 CNRS, UMR7104, 67404 Illkirch, France.
  • 4 4 Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France.
  • 5 5 John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
  • 6 6 Department of Pathology, McGill University Health Centre, Montreal Neurological Institute Hospital, Montreal, QC H3A 2B4, Canada.
  • 7 7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
  • 8 8 McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada.
  • 9 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 10 Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 11 11 Rare Neurological Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
  • 12 12 Department of Biology, University of York, Wentworth Way, York YO10 5DD, UK.
  • 13 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404 Illkirch, France [email protected] [email protected].
  • 14 7 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada [email protected] [email protected].
PMID: 27816943 DOI: 10.1093/brain/aww257
Abstract

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.

Keywords

MLTK; centronuclear myopathy; congenital myopathy; exome; kinase.

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