Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy. Issue 3 (8th January 2016)

• Record Type: Journal Article
• Authors: Brodehl, Andreas; Ferrier, Raechel A.; Hamilton, Sara J.; Greenway, Steven C.; Brundler, Marie‐Anne; Yu, Weiming; Gibson, William T.; McKinnon, Margaret L.; McGillivray, Barbara; Alvarez, Nanette; Giuffre, Michael; Schwartzentruber, Jeremy; Gerull, Brenda
• Is Part Of: Human mutation. Volume 37:Issue 3(2016)
• Page Start: 269
• Page End: 279
• Publication Date: 2016-01-08
• Subjects: restrictive cardiomyopathy -- filamin‐C -- heart failure -- exome sequencing -- FLNC; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22942
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : The article describes for the first time FLNC as a disease gene for familial restrictive cardiomyopathy (RCM). RCM is a heart muscle disease leading to heart failure at young ages often resulting in early heart transplantation. Two novel variants in FLNC have been discovered by next‐generation sequencing and show co‐segregation in two independent families. In addition, cytoplasmic protein aggregates were present in cardiac tissue of mutation carriers and in muscle cell lines expressing mutant filamin‐C. ABSTRACT: Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next‐generation sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin‐C ( FLNC ), an actin‐cross‐linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal‐dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin‐C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin‐C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal‐dominant RCM and broadens the phenotype spectrum of filaminopathies.