| First Author | Stonadge A | Year | 2023 |
| Journal | Hum Mol Genet | Volume | 32 |
| Issue | 17 | Pages | 2751-2770 |
| PubMed ID | 37427997 | Mgi Jnum | J:359716 |
| Mgi Id | MGI:7565967 | Doi | 10.1093/hmg/ddad113 |
| Citation | Stonadge A, et al. (2023) Myofibrillar myopathy hallmarks associated with ZAK deficiency. Hum Mol Genet 32(17):2751-2770 |
| abstractText | The ZAK gene encodes two functionally distinct kinases, ZAKalpha and ZAKbeta. Homozygous loss of function mutations affecting both isoforms causes a congenital muscle disease. ZAKbeta is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKbeta substrates in skeletal muscle or the mechanism whereby ZAKbeta senses mechanical stress remains 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, ZAKbeta appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and Filamin C (FLNC) in a phosphoproteomics assay and extended analyses suggested a role for ZAKbeta 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 ZAKbeta 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. |
