Novel pathogenic variants in filamin C identified in pediatric restrictive cardiomyopathy

Abstract

Restrictive cardiomyopathy (RCM) is a rare and distinct form of cardiomyopathy characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium, however, demonstrates impaired relaxation. To date, dominant variants causing RCM have been reported in a small number of sarcomeric or cytoskeletal genes, but the genetic causes in a majority of cases remain unexplained, especially in early childhood. Here, we describe two RCM families with childhood onset: one in a large family with a history of autosomal dominant RCM and the other a family with affected monozygotic, dichorionic/diamniotic twins. Exome sequencing found a pathogenic filamin C (FLNC) variant in each: p.Pro2298Leu, which segregates with disease in the large autosomal dominant RCM family, and p.Tyr2563Cys in both affected twins. In vitro expression of both mutant proteins yielded aggregates of FLNC containing actin in C2C12 myoblast cells. Recently, a number of variants in FLNC have been described that cause hypertrophic, dilated, and restrictive cardiomyopathies. Our data presented here provide further evidence for the role of FLNC in pediatric RCM, and suggest the need to include FLNC in genetic testing of cardiomyopathy patients including those with early ages of onset.

Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies

“…Same conclusions were drawn from the explanted hearts in the family with p.Y2563C mutation [ 57 ]. Conversely, the expression of filamin C variants in C2C12 cells led to aggregate formation [ 57 ]. Specifically, in cells expressing p.P2298L construct, aggregates were often observed in the proximity of nuclei [ 57 ].…”

“…Two more FLNC mutations have been reported in RCM families with childhood onset—c.6893C>T (p.P2298L) and c.7688A>G (p.Y2563C) [ 57 ]. The study of explanted cardiac tissue in the family with p.P2298L variant showed no inclusions or depositions and the sarcomere structure presented regular and without disarrays [ 57 ]. Same conclusions were drawn from the explanted hearts in the family with p.Y2563C mutation [ 57 ].…”

“…The study of explanted cardiac tissue in the family with p.P2298L variant showed no inclusions or depositions and the sarcomere structure presented regular and without disarrays [ 57 ]. Same conclusions were drawn from the explanted hearts in the family with p.Y2563C mutation [ 57 ]. Conversely, the expression of filamin C variants in C2C12 cells led to aggregate formation [ 57 ].…”

“…Conversely, the expression of filamin C variants in C2C12 cells led to aggregate formation [ 57 ]. Specifically, in cells expressing p.P2298L construct, aggregates were often observed in the proximity of nuclei [ 57 ]. On the other hand, C2C12 cells with p.Y2563C variant exhibited more punctate and varied in size—from (from small to intermediate—FLNC) FLNC aggregates [ 57 ].…”

Structure and Function of Filamin C in the Muscle Z-Disc

“…In conclusion, the mutations are distributed in all domains of FLNC protein having mutational hotspots in R24 (p.Trp2710Ter) that is found in patients from diverse ethnic origins [13,137]. Biochemical analysis revealed that many of the mutations lead to aggregation of FLNC proteins [99,121,137] (Figure 4). For example, expression of four FLNC mutants (p.V123A, p.A1539T, p.R2133H, and p.A2430V) in cardiac tissue culture cells resulted in the formation of actin aggregates, although FLNC p.A1539T mutant protein itself appears to be soluble [121].…”