Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms
作者： Malene E Lindholm , David Jimenez-Morales , Han Zhu , Kinya Seo , David Amar
DOI: 10.1101/2020.11.19.389064
关键词:
摘要: Abstract Alpha-actinin 2 (ACTN2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel reveal insights into the physiological function of ACTN2. Patient-derived iPSC-cardiomyocytes harboring protein-truncating variants were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, truncated protein incorporates sarcomeres, leading Z-disc structure. homozygous stop-gain affinity-purification mass spectrometry reveals an intricate interactome sarcomere sarcolemma-associated proteins. Loss C-terminus disrupts interaction ACTN1 GJA1, two proteins, that may lead clinical arrhythmic relaxation defects. causality mutation was verified using CRISPR-Cas9 gene editing. Together, these data advance our understanding role in human heart establish recessive inheritance truncation as causative disease.
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