Modeling Filamin C Mutations Causing Cardiomyopathy

Ohiri, Joyce Chimdinma

doi:https://doi.org/10.21985/n2-m4gv-km87

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Modeling Filamin C Mutations Causing Cardiomyopathy

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Heart failure is a growing clinical problem, and inherited cardiomyopathies contribute significantly to heart failure. Among the many genes associated with inherited cardiomyopathies, mutations in FLNC, the gene encoding the cytoskeletal protein filamin C, associate with a range of cardiomyopathy and increased risk for arrhythmia and sudden cardiac death in patients. Filamin C consists of three distinct domains: an actin-binding domain (ABD), a rod domain (RD), and a dimerization domain (DD). As a cytoskeletal protein, filamin C plays an important role in maintaining the structural integrity of the sarcomere in cardiac and skeletal muscle. Filamin C localizes at the Z-disk, an anchoring site for both titin and actin, and also at the sarcolemma. Proteostasis in an essential cellular process to maintain healthy protein quality control. Bcl-2-associated athanogene 3 (BAG3) mediates the autophagy pathway through its interaction with several heat shock factor proteins as a mechanism for proteostasis. However, it is not known what role the BAG3/filamin C interaction plays in the etiology of FLNC-linked DCM and arrhythmogenesis. I created novel physiological cell lines from patients with mutated FLNC and cardiomyopathy as well as gene edited FLNC isogenic cell lines. These induced pluripotent stem cell lines were differentiated to cardiomyocytes to directly measure the effect of loss of Filamin C on phenotypic expression. Proteotoxic and mechanical stressors were applied, and electrophysiological properties were measured to model the physiological responses of stressed cardiomyocytes in vitro. These studies showed that filamin C was required for a normal response to proteotoxic stress, and that in the absence of filamin C, cellular surrogate markers for arrhythmia were increased. This study contributes to the definition of clinical and molecular findings associated with mutation in FLNC.

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