Sudden cardiac death, arrhythmogenic cardiomyopathy and intercalated disc pathology due to reduced filamin C protein levels: a matter of life and death

Holtzhausen C, Heil L, Klingel K, Fox H, Gummert J, Gärtner A, Schmidt A, Krüger M, Kirfel G, Van Der Ven PF, Milting H, Clemen CS, Schröder R, Fürst DO, Tiesmeier J (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Human Molecular Genetics Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 34

Pages Range: 726-738

Journal Issue: 8

DOI: 10.1093/hmg/ddaf014

Abstract

Mutations in the human FLNC gene encoding filamin C (FLNc) cause a broad spectrum of sporadic and familial cardiomyopathies and myopathies. We report on the genetic, clinical, morphological and biochemical findings in a German family harboring an FLNC variant that leads to severe cardiac disease comprising sudden cardiac death and arrhythmogenic cardiomyopathy. Genetic analysis identified a novel heterozygous FLNC variant in exon 16 (NM_001458.4:c.2495_2498delAGTA, het; p.K832TfsX45) in i) the index patient suffering from dilated cardiomyopathy necessitating heart transplantation, ii) a son, who died from sudden cardiac death, iii) a second son, who survived an episode of sudden cardiac arrest and iv) a third son affected by isolated skeletal muscle myopathy. FLNc protein levels were markedly reduced in cardiac tissue obtained from the index patient, implying that the p.K832TfsX45 FLNc variant most probably caused nonsense-mediated decay of the corresponding mRNA. Morphological analysis of the diseased cardiac tissue revealed extensive fibrotic remodeling, and marked degenerative changes of the contractile apparatus of cardiomyocytes and severe structural alterations of intercalated discs. Connexin-43 signal intensity at intercalated discs was diminished and FLNc labelling of myofibrils was attenuated or even absent. Proteome analyses demonstrated complex alterations of extracellular matrix and intercalated disc proteins. Our findings demonstrate that this novel, truncating FLNC mutation likely leads to haploinsufficiency, thereby causing a deleterious sequence of degenerative changes of cardiac tissue with extensive fibrotic remodeling and intercalated disc pathology as the structural basis for FLNC-related cardiomyopathy with life-threatening cardiac arrhythmias.

Authors with CRIS profile

Christian Holtzhausen Department of Medicine 5 – Haematology and Oncology Rolf Schröder Professur für Neuropathologie

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Universitätsklinikum Tübingen DE Germany (DE) Herz- und Diabeteszentrum Nordrhein-Westfalen DE Germany (DE) Deutsches Zentrum für Luft- und Raumfahrt e.V. (DLR) / German Aerospace Center DE Germany (DE)

How to cite

APA:

Holtzhausen, C., Heil, L., Klingel, K., Fox, H., Gummert, J., Gärtner, A.,... Tiesmeier, J. (2025). Sudden cardiac death, arrhythmogenic cardiomyopathy and intercalated disc pathology due to reduced filamin C protein levels: a matter of life and death. Human Molecular Genetics, 34(8), 726-738. https://doi.org/10.1093/hmg/ddaf014

MLA:

Holtzhausen, Christian, et al. "Sudden cardiac death, arrhythmogenic cardiomyopathy and intercalated disc pathology due to reduced filamin C protein levels: a matter of life and death." Human Molecular Genetics 34.8 (2025): 726-738.

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