Thin filament mutations: Developing an integrative approach to a complex disorder

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90 Scopus citations

Abstract

Sixteen years ago, mutations in cardiac troponin (Tn)T and α-tropomyosin were linked to familial hypertrophic cardiomyopathy, thus transforming the disorder from a disease of the β-myosin heavy chain to a disease of the cardiac sarcomere. From the outset, studies suggested that mutations in the regulatory thin filament caused a complex, heterogeneous pattern of ventricular remodeling with wide variations in clinical expression. To date, the clinical heterogeneity is well matched by an extensive array of nearly 100 independent mutations in all components of the cardiac thin filament. Significant advances in our understanding of the biophysics of myofilament activation, coupled to the emerging evidence that thin filament linked cardiomyopathies are progressive, suggests that a renewed focus on the most proximal events in both the molecular and clinical pathogenesis of the disease will be necessary to achieve the central goal of using genotype information to manage affected patients. In this review, we examine the existing biophysical and clinical evidence in support of a more proximal definition of thin filament cardiomyopathies. In addition, new high-resolution, integrated approaches are presented to help define the way forward as the field works toward developing a more robust link between genotype and phenotype in this complex disorder.

Original languageEnglish (US)
Pages (from-to)765-782
Number of pages18
JournalCirculation research
Volume108
Issue number6
DOIs
StatePublished - Mar 18 2011
Externally publishedYes

Keywords

  • Cakinetics
  • familial cardiomyopathy
  • thin filaments

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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