Key result
Biallelic ALPK3 mutations cause severe early cardiomyopathy, while heterozygous truncating variants drive adult-onset HCM.
Why the study?
Pathogenic variants in ALPK3 cause cardiomyopathy with severity linked to zygosity, prompting a comprehensive review and systematic curation of clinical and experimental reports.
Systematic Review (n=209)
ALPK3 pathogenic variants result in a gene-dosage dependent spectrum of cardiomyopathies, with biallelic variants driving severe early-onset disease and heterozygous truncating mutations driving late-onset adult hypertrophic cardiomyopathy.
ALPK3 cardiomyopathy prognosis now requires zygosity assessment for counseling; extends prior reports by quantifying the biallelic-to-heterozygous phenotypic spectrum.
Pathogenic variants in ALPK3 (α-protein kinase 3), an atypical α‑kinase acting as a sarcomeric M-band scaffold, cause cardiomyopathy with severity linked to zygosity. We present a comprehensive review with systematic curation of peer-reviewed clinical and experimental reports through June 9, 2025, encompassing 156 patient-level variants and all published preclinical models. Biallelic loss-of-function variants lead to severe, often lethal cardiomyopathy with prenatal or early onset presentation and extracardiac involvement. Heterozygous protein-truncating variants, defined as nonsense or frameshift (resulting from insertion/deletion events or splicing mutations), explain ≈1% to 4% of adult hypertrophic cardiomyopathy, often with apical/septal hypertrophy, right ventricular involvement, fibrosis, and risk of progression. ALPK3 lacks catalytic activity and maintains sarcomeric proteostasis by scaffolding MYOMs (myomesins), MuRF (muscle ring-finger protein) E3 ligases, and SQSTM1 (sequestosome-1)/p62. Loss of this scaffolding function displaces MYOMs, drives thick‑filament protein aggregation, and precipitates severe contractile dysfunction in human induced pluripotent stem cell-derived cardiomyocytes and multiple mouse models. Therapeutic proof‑of‑concept has now been achieved on 2 fronts: (1) pharmacological correction of sarcomeric hypercontractility with the myosin inhibitor mavacamten and (2) durable phenotypic rescue in global knockout mice using an adeno-associated virus-delivered miniALPK3 gene‑replacement construct. Together, these data position ALPK3 cardiomyopathy as a compelling target for precision medicine. Early genetic diagnosis, genotype-tailored surveillance, and focused development of gene-replacement or editing strategies, potentially combined with modulators of the ALPK3-MuRF proteostatic axis, offer a realistic path to disease-modifying therapy for this once enigmatic condition.
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Chang et al. (2025) conducted a systematic review in ALPK3 Cardiomyopathy (n=209). ALPK3 pathogenic variants was evaluated on Clinical phenotype and disease progression based on variant zygosity. Biallelic ALPK3 mutations cause severe, early-onset cardiomyopathy with frequent transition from a dilated to hypertrophic phenotype, whereas heterozygous truncating variants predominantly lead to adult-onset hypertrophic cardiomyopathy.
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