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Polymorphisms in genes encoding nonsarcomeric proteins and their role in the pathogenesis of dilated cardiomyopathy

Polymorphismen in Genen, die für nichtsarkomerische Proteine kodieren, und deren Rolle in der Pathogenese der dilatativen Kardiomyopathie

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Abstract

Dilated cardiomyopathy (DCM), clinically characterized by contractile dysfunction and ventricular chamber enlargement, is a heterogeneous heart disease leading to progressive systolic heart failure and sudden cardiac death. The etiology of the disease is multifactorial and involves genetic factors, viral infections, autoimmune phenomena, and toxic agents. Within the last two decades, a growing body of evidence has suggested that single-gene mutations play a pivotal role in the development of familial forms of dilated cardiomyopathies. Numerous genes encoding cytoskeletal, sarcomeric, and nuclear proteins have been linked to the pathogenesis of DCM, and most of the respective mutants disrupt the structural integrity of sarcomeres in cardiac myocytes. Frequently, point mutations in cytoskeletal proteins critically diminish force generation and interfere with mechanical transduction within the contractile apparatus of the myocardium, thereby ultimately leading to impaired systolic function. However, hitherto reported sarcomeric gene defects explain the etiology of the disease only in some families, leaving other forms of DCM subentities unresolved. Since one of the major factors in DCM pathogenesis involves autoimmune-mediated damage to cardiac tissue, candidate genes that are involved in controlling immune reactions have currently come into focus in genetic research. We and others have shown that a single-nucleotide polymorphism (SNP) in the gene encoding cytotoxic T-lymphocyte antigen 4 (CTLA4) is associated with the diagnosis of DCM. Cytotoxic T-lymphocyte antigen 4 is an inhibitory receptor molecule expressed on activated T lymphocytes, where it functions as an important negative regulator of T-cell activation by competing with the costimulatory CD28 receptor to bind to B7 receptors localized on the surface of antigen-presenting cells. The observed association between CTLA4 genotypes and DCM suggests that genetic factors contribute to both unbalanced immune responses in the myocardium and the development of left ventricular dysfunction. In this review, we will briefly discuss how these findings may stimulate the search for novel DCM-associated SNPs in human genes expressed in noncardiomyocytes.

Zusammenfassung

Die dilatative Kardiomyopathie (DCM), klinisch charakterisiert durch eine Größenzunahme der Ventrikel mit kontraktiler Dysfunktion, ist ein heterogenes Krankheitsbild, das zu progredienter systolischer Herzinsuffizienz und plötzlichem Herztod führt. Die Ätiologie der Erkrankung ist multifaktoriell und beinhaltet genetische Ursachen, virale Infektionen, Mechanismen der Autoimmunität gegen kardiale Antigene und toxische Agenzien. Innerhalb der letzten zwei Dekaden ergab sich eine Vielzahl von Hinweisen darauf, dass einzelne Genmutationen eine wichtige Rolle bei der Entstehung von familiären Formen dilatativer Kardiomyopathien spielen. Zahlreiche für zytoskelettale, sarkomerische oder nukleäre Proteine kodierende Gene wurden mit der Pathogenese der DCM in Verbindung gebracht. Die meisten der entsprechenden Mutationen zerstören die strukturelle Integrität des Sarkomers in Kardiomyozyten. Häufig beeinträchtigen Punktmutationen in zytoskelettalen Proteinen die Kraftentwicklung und behindern die mechanische Kraftweiterleitung im kontraktilen Apparat des Myokards mit der langfristigen Folge einer systolischen Funktionsstörung. Defekte in myokardial exprimierten Genen können allerdings nur in einem Teil der familiären Fälle hinreichend die Ätiologie begründen, während andere Fälle von dilatativen Kardiomyopathien unerklärt bleiben. Da ein wesentlicher Faktor für die Pathogenese der DCM ein autoimmunologisch vermittelter Myokardschaden sein kann, gerieten solche Kandidatengene zunehmend in den Mittelpunkt des Interesses, die an der Kontrolle der Immunantwort beteiligt sind. In zwei Arbeiten wurde ein Einzelnukleotidpolymorphismus (SNP) im zytotoxischen Lymphozytenantigen 4 (CTLA4) mit der Diagnose einer DCM in Verbindung gebracht. CTLA4 ist ein auf aktivierten Lymphozyten exprimiertes Rezeptormolekül mit inhibitorischer Wirkung, welches als negativer Regulator der T-Zell-Aktivierung mit dem kostimulatorischen CD28-Rezeptor um die Bindung an B7-Rezeptoren auf der Oberfläche von antigenpräsentierenden Zellen konkurriert. Die beobachtete Assoziation von Genotypen des CTLA4-Rezeptors und der DCM deutet auf den Einfluss genetischer Faktoren bei dysregulierten Immunantworten und der Entwicklung einer linksventrikulären Funktionsstörung hin. In diesem Übersichtsartikel wird diskutiert, wie diese Beobachtungen die Suche nach neuen DCM-assoziierten SNPs in humanen, nicht myokardial exprimierten Genen befördern könnten.

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ArticleOpen access08 February 2025

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Acknowledgments

The authors gratefully acknowledge the excellent technical assistance of Clarissa Struwe and Jana Petersen from the University of Marburg.

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On behalf of all authors, the corresponding author states that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Psychosomatic Medicine and Psychotherapy, German Centre for Cardiovascular Research, University of Göttingen, Waldweg 33, 37073, Göttingen, Germany

    J. Staab &  T. Meyer

  2. Department of Internal Medicine and Cardiology, Philipps University and UKGM GmbH Marburg, Marburg, Germany

    V. Ruppert & S. Pankuweit

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  1. J. Staab

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  2. V. Ruppert

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  3. S. Pankuweit

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  4. T. Meyer

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Correspondence to T. Meyer.

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This article is dedicated to Professor Emeritus Bernhard Maisch, former Head of the Department of Cardiology at the University of Marburg and Editor of HERZ, on the occasion of his retirement.

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Staab, J., Ruppert, V., Pankuweit, S.et al. Polymorphisms in genes encoding nonsarcomeric proteins and their role in the pathogenesis of dilated cardiomyopathy.Herz37, 836–842 (2012). https://doi.org/10.1007/s00059-012-3698-6

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