Variants in the alpha kinase 3 (ALPK3) gene cause cardiomyopathy, but we have little understanding of the mechanisms at play. We demonstrate that ALPK3 forms a critical signaling node that links contractile proteins to protein quality control machinery. These findings may open new therapeutic approaches to treat cardiomyopathies.
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References
Almomani, R. et al. Biallelic truncating mutations in ALPK3 cause severe pediatric cardiomyopathy. J. Am. Coll. Cardiol. 67, 515–525 (2016). This clinical case study was one of the first studies to report ALPK3 as a cardiomyopathy gene.
Phelan, D. G. et al. ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy. Eur. Heart J. 37, 2586–2590 (2016). This article reports a pediatric case of ALPK3-associated cardiomyopathy and uses hPSC models to show abnormal calcium handling.
Hosoda, T. et al. A novel myocyte-specific gene Midori promotes the differentiation of P19CL6 cells into cardiomyocytes. J. Biol. Chem. 276, 35978–35989 (2001). The first paper to clone and characterize the ALPK3 gene.
Agarwal, R. et al. Pathogenesis of cardiomyopathy caused by variants in ALPK3, an essential pseudokinase in the cardiomyocyte nucleus and sarcomere. Circulation 146, 1674–1693 (2022). A recent paper that described ALPK3 as a nuclear and sarcomeric pseudokinase.
Lopes, L. R. et al. Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy. Eur. Heart J. 42, 3063–3073 (2021). This article reported a cohort of patients carrying autosomal dominant ALPK3 truncating variants associated with adult-onset hypertrophic cardiomyopathy.
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This is a summary of: McNamara, J. W. et al. Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle. Nat. Cardiovas. Res. https://doi.org/10.1038/s44161-023-00219-9 (2023).
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Alpha kinase 3 signaling is required at the sarcomeric M-band for cardiac function. Nat Cardiovasc Res 2, 110–111 (2023). https://doi.org/10.1038/s44161-023-00221-1
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DOI: https://doi.org/10.1038/s44161-023-00221-1
