PDF(Pubmed)
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.
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.
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.
摘要：
背景：许多心肌病相关的FLNC致病变异体是杂合截短，和FLNC致病变异与心律失常有关。丝胺病中的心律失常触发因素尚未完全了解。
结果：我们描述了一个具有双等位基因FLNC致病变体的个体，p.Arg650Xandc.970-4A>G,伴有围产期心肌病和室性心律失常.我们还描述了具有FLNC变体的先证者的临床发现，包括Val2715fs87X，Glu2458Serfs71X,Phe106Leu,c.970-4A>G伴有肥厚性和扩张型心肌病，心房颤动,室性心动过速.产生诱导多能干细胞衍生的心肌细胞(iPSC-CM)。FLNC截断，Arg650X/c.970-4A>G，显示丝素C蛋白显着减少，与功能突变的双等位基因丧失一致。为了评估丝素C的损失，健康对照iPSC系的基因编辑用于在肌动蛋白结合结构域中产生纯合FLNC破坏。因为丝状蛋白C与蛋白质质量控制有关，我们评估了iPSC-CM中丝素C对蛋白酶体抑制剂硼替佐米反应的必要性.暴露于低剂量硼替佐米后,FLNC-nulliPSC-CM显示伴娘蛋白BAG3，HSP70（热休克蛋白70）的增加，和HSPB8(小热休克卵白B8)和自噬标志LC3I/II。FLNC零iPSC-CM具有延长的电场电势，在低剂量硼替佐米的存在下进一步延长。低剂量硼替佐米后，FLNC无效工程心脏组织功能受损。
结论：FLNC致病变异与心律失常倾向相关，可以在iPSC-CM中建模。丝素C延长场电位的降低，动作电位的代理人，以及硼替佐米诱导的蛋白酶体抑制，减少的丝素C导致更大的心律失常潜力和功能受损。
结果：我们描述了一个具有双等位基因FLNC致病变体的个体，p.Arg650Xandc.970-4A>G,伴有围产期心肌病和室性心律失常.我们还描述了具有FLNC变体的先证者的临床发现，包括Val2715fs87X，Glu2458Serfs71X,Phe106Leu,c.970-4A>G伴有肥厚性和扩张型心肌病，心房颤动,室性心动过速.产生诱导多能干细胞衍生的心肌细胞(iPSC-CM)。FLNC截断，Arg650X/c.970-4A>G，显示丝素C蛋白显着减少，与功能突变的双等位基因丧失一致。为了评估丝素C的损失，健康对照iPSC系的基因编辑用于在肌动蛋白结合结构域中产生纯合FLNC破坏。因为丝状蛋白C与蛋白质质量控制有关，我们评估了iPSC-CM中丝素C对蛋白酶体抑制剂硼替佐米反应的必要性.暴露于低剂量硼替佐米后,FLNC-nulliPSC-CM显示伴娘蛋白BAG3，HSP70（热休克蛋白70）的增加，和HSPB8(小热休克卵白B8)和自噬标志LC3I/II。FLNC零iPSC-CM具有延长的电场电势，在低剂量硼替佐米的存在下进一步延长。低剂量硼替佐米后，FLNC无效工程心脏组织功能受损。
结论：FLNC致病变异与心律失常倾向相关，可以在iPSC-CM中建模。丝素C延长场电位的降低，动作电位的代理人，以及硼替佐米诱导的蛋白酶体抑制，减少的丝素C导致更大的心律失常潜力和功能受损。
