Affiliation:
1. Center for Genetic Medicine, Feinberg School of Medicine Northwestern University Chicago IL USA
2. Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine Northwestern University Chicago IL USA
3. Bluhm Cardiovascular Institute Northwestern Medicine Chicago IL USA
4. Cell and Molecular Physiology Loyola University Stritch School of Medicine Maywood IL USA
5. Department of Pharmacology, Feinberg School of Medicine Northwestern University Chicago IL USA
Abstract
Background
Many cardiomyopathy‐associated
FLNC
pathogenic variants are heterozygous truncations, and
FLNC
pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.
Methods and Results
We describe an individual with biallelic
FLNC
pathogenic variants, p.Arg650X and c.970‐4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with
FLNC
variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970‐4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) were generated. The
FLNC
truncation, Arg650X/c.970‐4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous
FLNC
disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC‐CMs for response to the proteasome inhibitor bortezomib. After exposure to low‐dose bortezomib,
FLNC‐
null iPSC‐CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II.
FLNC
null iPSC‐CMs had prolonged electric field potential, which was further prolonged in the presence of low‐dose bortezomib.
FLNC
null engineered heart tissues had impaired function after low‐dose bortezomib.
Conclusions
FLNC
pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC‐CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib‐induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.
Publisher
Ovid Technologies (Wolters Kluwer Health)