Journal of Clinical Medicine Review Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy Matthias Eden 1,2 and Norbert Frey 1,2,* 1 Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, Germany; [email protected] 2 German Centre for Cardiovascular Research, Partner Site Heidelberg, 69120 Heidelberg, Germany * Correspondence: [email protected] Abstract: Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combi- nations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from “bench to bedside” can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death. These advances provide not only mechanistic insights into the earliest manifestations of cardiomyopathy, but such efforts also hold the promise that mutation-specific pathophysiology might result in novel “personalized” therapeutic possibilities. Recently, the FLNC gene encoding the sarcomeric protein filamin C has gained special interest since FLNC mutations were found in several distinct and possibly overlapping cardiomyopathy phenotypes. Specifically, mutations in FLNC were initially only linked to myofibrillar myopathy (MFM), but are now increasingly found in various forms of human cardiomyopathy. FLNC thereby Citation: Eden, M.; Frey, N. Cardiac represents another example for the complex genetic and phenotypic continuum of these diseases. Filaminopathies: Illuminating the Divergent Role of Filamin C Keywords: filamin C; cardiomyopathy; gene mutations Mutations in Human Cardiomyopathy. J. Clin. Med. 2021, 10, 577. https://doi.org/10.3390/ jcm10040577 1. Introduction Academic Editor: Stefan Peters Human cardiomyopathies in general can be classified into primary and secondary Received: 5 January 2021 cardiomyopathies. Within this classification, primary cardiomyopathies can be subdivided Accepted: 2 February 2021 into pure genetic forms like hypertrophic cardiomyopathy (HCM), arrhythmogenic right Published: 4 February 2021 ventricular cardiomyopathy (ARVC), and left ventricular non-compaction cardiomyopathy (LVNCM) as well as Ion channel, conduction, and storage disorders. Dilated cardiomy- Publisher’s Note: MDPI stays neutral opathies (DCM) as well as restrictive cardiomyopathy (RCM) are categorized in to mixed with regard to jurisdictional claims in primary cardiomyopathies, since a potential genetic etiology explains only a part of these published maps and institutional affil- clinical entities [1–5]. iations. As it has been previously described for filamin A (FLNA) and B (FLNB), filamin C (FLNC) is also recognized as an important structural crosslinker of actin rods at the sarcomeric z-disc of both cardiac and skeletal muscle [6]. Moreover, all three filamin variants reveal high sequence similarities indicating similar cellular functions. While Copyright: © 2021 by the authors. FLNA and FLNB are ubiquitously expressed, FLNC is predominantly enriched in cardiac Licensee MDPI, Basel, Switzerland. and skeletal muscle. Of note, dimerization of two identical filamins through their Ig-like This article is an open access article domains 24 is crucial for correct filamin function (Figure1)[ 4,7]. For all three filamins, a distributed under the terms and subcellular localization at the sarcomeric z-disc, intercalated discs, cell-membranes, and conditions of the Creative Commons myotendinous junctions has been described. It is speculated that, due to their structural Attribution (CC BY) license (https:// characteristics, in particular filamin A and filamin C also can serve as a nodal point for creativecommons.org/licenses/by/ sarcomeric mechanotransduction in different muscle cells [7,8]. 4.0/). J. Clin. Med. 2021, 10, 577. https://doi.org/10.3390/jcm10040577 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 9 J. Clin. Med. 2021, 10, 577 nous junctions has been described. It is speculated that, due to their structural character-2 of 8 istics, in particular filamin A and filamin C also can serve as a nodal point for sarcomeric mechanotransduction in different muscle cells [7,8]. Figure 1. SchematicSchematic structure structure of filamins filamins as mechanosensor. SchematicSchematic structure ofof FilaminsFilamins bindingbinding and and cross-linking cross-linking F-actin F-actin via via N-terminal N-terminal Actin Ac- tinBinding Binding Domains Domains (ABD; (ABD; blue) blue containing) containing Actin Actin Binding Binding Sites (ABS).Sites (ABS). Distinct Distinct regions regions within withinrod 1 (R3–5; rod 1 violet)(R3–5; andviolet) rod and 2 (R16–21) rod 2 (R16–21) are prone are to prone spring-like to spring-like conformational conformational changes. changes.Domains Domains highlighted highlighted in orange in are orange possible are interaction possible interaction sites for z-disc sites proteins,for z-disc domain proteins, 21 domain(green) represents21 (green) therepresents possible the interaction possible site inte withraction integrins. site with Domains integrins. R22–23 Domains interact R22–23 with interactsarcoglycans with sarcoglycans (yellow). The (yellow). proposed The model proposed shows model that contractile shows that force contractile and deformation force and deformationof actin networks of actin induce networks conformational induce confor changesmational of both changes filamin of dimers. both filamin Subsequently, dimers. Subsequently,some binding some partners binding are able partners to interact are able with to interact exposed with binding exposed sites binding under mechanicalsites under mechanicalstress, whereas stress, some whereas will rather some dissociatewill rather under dissociate conformational under conformational change [7,8 change]. [7,8]. FilaminFilamin C C was was first first reported reported to to be be associated associated with with various various forms forms of of skeletal skeletal myopathy myopathy (i.e.,(i.e., MFM) MFM) [7]. [7]. The The encoding encoding FLNCFLNC genegene consists consists of of 48 48 coding exons and is located on chromosomechromosome 7q32–35. 7q32–35. Two Two isoforms (one shorte shorterr isoform, lacking exon 31 and predicted toto be be less less flexible) flexible) have have been been partially partially characterized characterized so so far. far. The The shorter shorter Isoform is thought toto be expressed 3.53.5 timestimes higherhigher in in skeletal skeletal than than cardiac cardiac muscle, muscle, whereas whereas the the longer longer filamin fila- minC isoform C isoform seems seems less less abundant abundant in cardiomyocytes in cardiomyocytes under under basal basal conditions conditions but but is rapidly is rap- idlyinduced induced upon upon cardiac cardiac stress. stress. More More than than 90 potential 90 potential binding binding partners partners for filamin for filamin C have C havebeen been denoted denoted in the in current the current literature literature [6,7]. [6,7 At sarcomeric]. At sarcomeric z-discs, z-discs, filamin filamin C interacts C interacts with withvarious various proteins proteins partially partially linked linked to inherited to inherited cardiomyopathies cardiomyopathies like calsarcins like calsarcins (Involved (In- in volvedHCM [ 9in–11 HCM]), myopalladin [9–11]), myopalladin (linked to RCM(linked [12 to]), RCM cypher [12]), (linked cypher to ARVC(linked and to ARVC DCM [ 13and]), DCMactin (linked[13]), actin to DCM(linked [14 to]), DCM myotilin, [14]), myopodin,myotilin, myopodin, and others. and Moreover, others. Moreover, filamin Cfilamin binds Cto binds the sarcolemma to the sarcolemma via integrin-1 via integrin-1β and sarcoglycan-deltaβ and sarcoglycan-delta (knownas (known part of as the part muscular of the musculardystrophin dystrophin complex) [complex)15,16]. Filamin [15,16]. C Filamin can be cleaved C can be by clea theved protease by the calpain protease in ordercalpain to indifferentially order to differentially regulate the regulate sarcoglycan-filamin the sarcoglycan-filamin interaction. interaction. − − InIn mice,mice, lossloss of ofFLNC FLNCfunction function leads leads to diverse to diverse results. results. Whereas Whereas partial partialFLNC FLNC/ mice −/−, mice,expressing expressing a truncated a truncated filamin filamin C by C deletionby deletion of of exons exons 41–48, 41–48, show show a a severesevere muscular phenotype, leading to lethality due to respiratory failure, before birth, they displayed no obvious cardiac defects [17]. In contrast, a recent publication stressed the crucial role for cardiac filamin C in mice, analyzing multiple, complete FLNC knockout mouse J. Clin. Med. 2021, 10, 577 3 of 8 models [18]. In contrast to the partial FLNC knockout, they generated conventional and heart restricted knockouts in which Cre-mediated deletion of the FLNC region between exons 9 and 13 resulted in subsequent frameshift of FLNC and, thereby, complete loss of the protein. Since these global and heart restricted FLNC −/− mice were embryonic lethal, additional inducible heart restricted FLNC knockout mice were