Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies

Ortíz-Genga, Martín; Cuenca, Sofía; Ferro, Matteo Dal; Zorio, Esther; Salgado-Aranda, Ricardo; Climent, Vicente; Padrón-Barthe, Laura; Duro-Aguado, Iria; Jiménez‐Jáimez, Juan; Hidalgo-Olivares, Víctor M.; García-Campo, Enrique; Lanzillo, Chiara; Suárez-Mier, M. Paz; Yonath, Hagith; Marcos‐Alonso, Sonia; Ochoa, Juan Pablo; Santomé, José L.; García-Giustiniani, Diego; Rodríguez-Garrido, Jorge; Domínguez, Fernándo; Merlo, Marco; Palomino, Julián; Peña, María Luisa Peña; Trujillo, Juan Pablo Fernández; Martín-Vila, Alicia; Stolfo, Davide; Molina, Pilar; Lara‐Pezzi, Enrique; Calvo-Iglesias, Francisco; Nof, Eyal; Calò, Leonardo; Barriales‐Villa, Roberto; Gimeno-Blanes, Juan Ramón; Arad, Michael; García‐Pavía, Pablo; Monserrat, Lorenzo

doi:10.1016/j.jacc.2016.09.927

Cited by 389 publications

(387 citation statements)

References 27 publications

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“…None of these reports indicated any observed cardiac phenotype. More recently, the impact of FLNC variation on the heart has been recognized, including reports on dilated cardiomyopathy, 34–36 hypertrophic cardiomyopathy, 37,38 atrial fibrillation, 37,39 and restrictive cardiomyopathy. 9 The phenotypic spectrum associated with FLNC variation is intriguing, suggesting that variants act through divergent and tissue specific manner and/or that variants are modified by other genetic factors present in the given family.…”

Section: Discussionmentioning

confidence: 99%

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Tucker

McLellan

et al. 2017

Circ Cardiovasc Genet

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Background Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. Methods and Results We evaluated 8 family members across four generations by history, physical examination, electrocardiography and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (p.V2297M). FLNC encodes Filamin C, a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle, and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of Filamin C localization in cardiac tissue from an affected family member revealed a diminished localization at the z-disk, whereas traditional localization at the intercalated disk was preserved. Stem-cell derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared to controls. Conclusion We have identified a novel variant in FLNC as pathogenic variant for familial RCM, a finding that further expands upon the genetic basis of this rare and morbid cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Novel Mutation in FLNC (Filamin C) Causes Familial Restrictive Cardiomyopathy

Tucker

McLellan

et al. 2017

Circ Cardiovasc Genet

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“…Recently, filamin C was also shown to mediate fast repair of myofibrillar microdamage in cardiomyocytes, in addition to Z-disk assembly [24] . Filamin C predominantly consists of 24 immunoglobulin-like domains spanning over 80% of the protein, with an actin-binding domain at the amino terminus and a dimerization domain at the carboxy terminus.…”

Section: Discussionmentioning

confidence: 99%

“…Filamin C predominantly consists of 24 immunoglobulin-like domains spanning over 80% of the protein, with an actin-binding domain at the amino terminus and a dimerization domain at the carboxy terminus. The Ig-like domain region has been found to interact with over 90 proteins [24] . Initially, dominant disruptive mutations in FLNC were found in association with skeletal muscle phenotypes (OMIM no.…”

Section: Discussionmentioning

confidence: 99%

“…Among the reports of FLNC-related cardiomyopathy where the patients were ascertained due to heart phenotype, there was only one report of patients also having symptoms of skeletal myopathy or detection of protein deposits in skeletal muscle [30] . The predominantly-cardiac phenotype mutations include missense substitutions and truncating mutations are in functional domains scattered across the gene; the truncating mutations are thought to exert pathogenesis through haploinsufficiency rather than protein aggregation [24] . In patients with predominantly (or only) skeletal muscle myopathy, the mutations reported (A193T, M251T, in-frame p.Val930_Thr933del, F1720LfsX63, T2419M, and W2710X), are in regions and functional domains distinct from the cardiac-only reports, thus likely affecting the protein function differently such that cardiac muscle is preferentially spared [34,35] .…”

Section: Discussionmentioning

confidence: 99%

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Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

Sanoja¹,

Li²,

Fricker³

et al. 2018

JTGG

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Aim: Idiopathic cardiomyopathy is often genetic in origin, typically autosomal dominant, and restrictive cardiomyopathy (RCM) is the rarest form. Clinically, RCM prognosis is poor with most patients requiring heart transplant due to impaired diastolic function leading to heart failure. In some cases, desminopathy is also observed, whereby desmin protein aggregates in the myocardium. Many genes are known to be involved in cardiomyopathy, and we sought to find the pathogenic mutation of a four-generation family with RCM and desminopathy. Methods:We employed whole exome sequence analysis of four RCM patients from the family, to identify the underlying pathogenic mutation(s).Results: Analysis of the exome data led to identification of two putative pathogenic variants. One, a nonsense mutation in ADD3, encoding adducin 3, was found in the proband and his affected daughter, but not other family members. The other was a missense mutation (G1546S) in the gene encoding filamin C (FLNC), found in all of the affected individuals. Both of these proteins interact with proteins involved in sarcomere function, and are expressed in both heart and skeletal muscle. FLNC has recently been implicated as a cardiomyopathy gene, but ADD3 has not at this point. Conclusion:We present bioinformatic analyses that suggest that the FLNC variant is the major pathogenic variant affecting this family, but cannot rule out some contribution of the ADD3 mutation in at least two patients.

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“…Clear family segregation could not be documented for either of these, and thus their contribution to HCM could not be determined. Recently, FLNC mutations, especially truncations, have been linked to HCM and other cardiomyopathy phenotypes, and FLNC truncations appear to impart a greater risk for ventricular arrhythmias 8, 12 . Because the contributions of FLNC mutations have more recently been linked to HCM, FLNC is only now being incorporated into targeted gene panel testing.…”

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confidence: 99%