A novel MAP3K20 mutation causing centronuclear myopathy-6 with fiber-type disproportion in a Pakistani family

Ahmad, Ilyas; Khan, Ayaz; Ayan, Hafiza Noor Ul; Budde, Birgit; Altmüller, Janine; Korejo, Asad Aslam; Nürnberg, Gudrun; Thiele, Holger; Tariq, Muhammad; Nürnberg, Peter; Erdmann, J.

doi:10.1038/s10038-022-01085-2

Cited by 3 publications

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“…Loss of function of Zak causes a mild disease in mice compared with the congenital myopathy condition described in humans ( 11 , 35 ). Zak −/− mice do not show any overt difference to controls, including in behavioural tests ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Myofibrillar myopathy hallmarks associated with ZAK deficiency

Stonadge

Genzor

Russell

et al. 2023

Human Molecular Genetics

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The ZAK gene encodes two functionally distinct kinases, ZAKɑ and ZAKβ. Homozygous loss of function mutations affecting both isoforms cause a congenital muscle disease. ZAKβ is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKβ substrates in skeletal muscle or the mechanism whereby ZAKβ senses mechanical stress remain to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKβ appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and FLNC in a phosphoproteomics assay and extended analyses suggested a role for ZAKβ in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKβ signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK-deficiency.

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Section: Discussionmentioning

confidence: 99%