%0 Journal Article
%T Reduction of Filamin C Results in Altered Proteostasis, Cardiomyopathy, and Arrhythmias.
%A Ohiri JC
%A Dellefave-Castillo L
%A Tomar G
%A Wilsbacher L
%A Choudhury L
%A Barefield DY
%A Fullenkamp D
%A Gacita AM
%A Monroe TO
%A Pesce L
%A Blancard M
%A Vaught L
%A George AL
%A Demonbreun AR
%A Puckelwartz MJ
%A McNally EM
%J J Am Heart Assoc
%V 13
%N 10
%D 2024 May 21
%M 38761081
%F 6.106
%R 10.1161/JAHA.123.030467
%X <B>BACKGROUND: </B>Many cardiomyopathy-associated FLNC pathogenic variants are heterozygous truncations, and FLNC pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.