Disease modeling of a mutation in α-actinin 2 guides clinical therapy in hypertrophic cardiomyopathy.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding α-actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient-derived human-induced pluripotent stem cells (hiPSCs) and show that hiPSC-derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca²⁺ sensitivity, and also prolonged action potential duration and enhanced L-type Ca²⁺ current. The L-type Ca²⁺ channel blocker diltiazem reduced force am

SUBMITTER: Prondzynski M 

PROVIDER: S-EPMC6895603 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature