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

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  • Nasim Vasli
  • Elizabeth Harris
  • Jason Karamchandani
  • Eric Bareke
  • Jacek Majewski
  • Norma B Romero
  • Tanya Stojkovic
  • Rita Barresi
  • Hichem Tasfaout
  • Richard Charlton
  • Edoardo Malfatti
  • Johann Bohm
  • Chiara Marini-Bettolo
  • Karine Choquet
  • Marie-Josée Dicaire
  • Yi-Hong Shao
  • Ana Topf
  • Erin O'Ferrall
  • Bruno Eymard
  • Volker Straub
  • Hanns Lochmüller
  • Bernard Brais
  • Jocelyn Laporte
  • Martine Tétreault


Publication details

JournalBrain : a journal of neurology
DateAccepted/In press - 31 Aug 2016
DateE-pub ahead of print - 5 Nov 2016
DatePublished (current) - 1 Jan 2017
Issue number1
Number of pages12
Pages (from-to)37-48
Early online date5/11/16
Original languageEnglish


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.

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© 2016, The Authors. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details

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