Abstract
Genetic mutations lead to cardiomyopathy, a condition linked to heart failure and arrhythmias.Mutations in the FLNC gene have recently been reported in multiple forms of cardiomyopathyincluding dilated, hypertrophic and restrictive forms. The FLNC gene encodes filamin C, anactin-binding protein highly expressed in the heart and skeletal muscle. Filamin C is comprisedof three domains: an actin-binding domain at the N-terminus, a rod domain consisting of 24 Igrepeats in the mid region, and a dimerization domain at the C-terminus. Missense mutations in FLNC have also been described in myofibrillar myopathy, a disorder in skeletal musclecharacterized by intracellular aggregates within muscle. Where examined, FLNC mutant heartsdo not have evident protein aggregation leading to the hypothesis that FLNC mutations havedifferent modes of action in skeletal and cardiac muscle. We identified a FLNC Val2715fs87Xmutation in a 55 yo M with cardiac fibrosis and a history of arrhythmias. We found a second FLNC mutation, Glu2458SerfsX71, which was found in a family with sudden death andhypertrophic cardiomyopathy. A third FLNC mutation, Arg650X, was found in a 41 yo F withhistory of postpartum cardiomyopathy; this patient also harbors a second FLNC variant ofuncertain significance, intron 5, c.970-4A>G (Intronic), which is predicted to affect splicing onher other FLNC allele. Notably, this patient was diagnosed with a muscle disorder in early life.Finally, a fourth FLNC variant, Phe106Leu, found in two brothers with skeletal and cardiacmyopathy was also studied. To examine the mechanisms by which FLNC mutations causecardiomyopathy, we generated patient-derived induced pluripotent stem cells (iPSCs) anddifferentiated these cell lines into cardiomyocytes. Cardiomyocyte function was analyzed usingautomated field potential measurements with the Nanion CardioExcyte. We identified a slowerrate of repolarization with FLNC truncations compared to control. These data demonstrate thepathogenic findings associated with FLNC mutations and provide mechanistic insight intocardiomyopathy and arrhythmias resulting from these mutations.
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