Key result
Actn2 p.Met228Thr causes embryonic lethality in homozygotes and induces hypertrophic cardiomyopathy features in heterozygous mice.
Why the study?
Pathogenic variants in ACTN2 are known to cause hypertrophic cardiomyopathy, but little is known about the underlying disease mechanisms.
The ACTN2 p.Met228Thr variant causes protein instability and ubiquitin-proteasomal system activation, leading to embryonic lethality in homozygous mice and molecular signs of cardiomyopathy in mature heterozygous males.
May inform ACTN2 variant interpretation in HCM; leaves open human translation and therapeutic targeting.
Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hypertrophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr variant were phenotyped by echocardiography. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Resolution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormalities in sarcomeric parameters, cell-cycle defects and mitochondrial dysfunction. The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteasomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteasomal system is activated; a mechanism that has been implicated in cardiomyopathies previously. In parallel, a lack of functional alpha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell-cycle defects, the likely cause of the death of the embryos. The defects also have wide-ranging morphological consequences.
No takes yet. Share an insight, caveat, or question.
Broadway‐Stringer et al. (2023) studied Hypertrophic Cardiomyopathy. Actn2 p.Met228Thr variant vs. Wild-type littermates was evaluated on Phenotypic and molecular characterization. The Actn2 p.Met228Thr variant is embryonically lethal in homozygous mice due to morphological and molecular defects, while mature heterozygous males display molecular features of hypertrophic cardiomyopathy.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: