From the sarcomere to the nucleus: Role of genetics and signaling in structural heart disease

R. L. Nicol, N. Frey, E. N. Olson

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


The identification of genetic mutations underlying familial structural heart disease has provided exciting new insights into how alterations in structural components of the cardiomyocyte lead to different forms of cardiomyopathy. Specifically, mutations in components of the sarcomere are frequently associated with hypertrophic cardiomyopathy, whereas mutations in cytoskeletal proteins lead to dilated cardiomyopathy. In addition, extrinsic stresses such as hypertension and valvular disease can produce myocardial remodeling that is very similar to that observed in genetic cardiomyopathy. For myocardial remodeling to occur, changes in gene expression must occur; therefore, changes in contractile function or wall stress must be communicated to the nucleus via signal transduction pathways. The identity of these signaling pathways has become a key question in molecular biology. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the β-adrenergic receptor, Gαq and downstream effectors, mitogen-activated protein kinase pathways, and the Ca2+-regulated phosphatase, calcineurin. In the past it has been difficult to discern which signaling molecules actually contributed to disease progression in vivo; however, the development of numerous transgenic and knockout mouse models of cardiomyopathy is now allowing the direct testing of stimulatory and inhibitory molecules in the mouse heart. From this work it has been possible to identify signaling molecules and pathways that are required for different aspects of disease progression in vivo. In particular, a number of signaling pathways have now been identified that may be key regulators of changes in myocardial structure and function in response to mutations in structural components of the cardiomyocyte. Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underly heart disease.

Original languageEnglish (US)
Pages (from-to)179-223
Number of pages45
JournalAnnual Review of Genomics and Human Genetics
Issue number2000
StatePublished - Jan 1 2000


  • Cardiac hypertrophy
  • Sarcomere
  • Signal transduction
  • Structural cardiomyopathy
  • Transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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