Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion
| Autor: | Rita Barresi, Norma B. Romero, Jacek Majewski, Edoardo Malfatti, Eric Bareke, Yi-Hong Shao, Ana Töpf, Johann Böhm, Karine Choquet, Jocelyn Laporte, Chiara Marini-Bettolo, Nasim Vasli, Tanya Stojkovic, Erin K. O'Ferrall, Volker Straub, Bruno Eymard, Richard Charlton, Gonzalo Blanco, Jason Karamchandani, Hanns Lochmüller, E. Harris, Martine Tétreault, Marie-Josée Dicaire, Bernard Brais, Hichem Tasfaout |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Pathology medicine.medical_specialty Nonsense mutation Biology Frameshift mutation Consanguinity 03 medical and health sciences 0302 clinical medicine medicine Humans Exome Centronuclear myopathy Exome sequencing Muscle weakness Original Articles MAP Kinase Kinase Kinases medicine.disease Congenital myopathy Hypotonia Pedigree Muscle Fibers Slow-Twitch 030104 developmental biology Muscle Fibers Fast-Twitch Mutation Female Neurology (clinical) medicine.symptom Protein Kinases 030217 neurology & neurosurgery Myopathies Structural Congenital |
| ISSN: | 1460-2156 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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