Filamin C (FLNC) is an actin-binding protein encoded by the FLNC gene. It is crucial for maintaining the structural integrity of the sarcomere and is involved in cell signaling within muscle cells. FLNC also plays a role in the Hippo signaling pathway, influencing muscle cell proliferation, migration, and differentiation [3].

Mutations in FLNC are associated with various cardiac and muscular phenotypes. Truncating variants, which can lead to haploinsufficiency, are often linked to dilated cardiomyopathy (DCM) and cardiac arrhythmias, with a high risk of sudden cardiac death. These truncating mutations cause an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies [2]. Missense variants, on the other hand, are more commonly associated with hypertrophic cardiomyopathy (HCM) and cluster in the ROD2 domain, which is important for sarcomere binding and cell signaling [1]. In myofibrillar myopathy (MFM), mutant FLNC is misfolded, unable to form homodimers or heterodimers, leading to protein aggregation in muscle fibers [4].

In conclusion, FLNC is essential for the normal function of muscle cells, especially in maintaining sarcomere stability and regulating muscle-related cellular processes. The study of FLNC-associated mutations in models helps in understanding the pathogenesis of cardiomyopathies and myopathies, highlighting its significance in these disease areas [1,2,4].

References:

1. Verdonschot, Job A J, Vanhoutte, Els K, Claes, Godelieve R F, Krapels, Ingrid P C, Brunner, Han G. 2020. A mutation update for the FLNC gene in myopathies and cardiomyopathies. In Human mutation, 41, 1091-1111. doi:10.1002/humu.24004. https://pubmed.ncbi.nlm.nih.gov/32112656/

2. Ortiz-Genga, Martín F, Cuenca, Sofía, Dal Ferro, Matteo, García-Pavía, Pablo, Monserrat, Lorenzo. . Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies. In Journal of the American College of Cardiology, 68, 2440-2451. doi:10.1016/j.jacc.2016.09.927. https://pubmed.ncbi.nlm.nih.gov/27908349/

3. Knyazeva, Anastasia, Khudiakov, Aleksandr, Vaz, Raquel, Sejersen, Thomas, Kostareva, Anna. 2020. FLNC Expression Level Influences the Activity of TEAD-YAP/TAZ Signaling. In Genes, 11, . doi:10.3390/genes11111343. https://pubmed.ncbi.nlm.nih.gov/33202721/

4. Kley, Rudolf Andre, Leber, Yvonne, Schrank, Bertold, Fürst, Dieter O, Vorgerd, Matthias. 2021. FLNC-Associated Myofibrillar Myopathy: New Clinical, Functional, and Proteomic Data. In Neurology. Genetics, 7, e590. doi:10.1212/NXG.0000000000000590. https://pubmed.ncbi.nlm.nih.gov/34235269/