The 'final common pathway' hypothesis and inherited cardiovascular disease

The role of cytoskeletal proteins in dilated cardiomyopathy

Neil E. Bowles, Karla R. Bowles, Jeffrey Towbin

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

The genetic basis of a number of inherited cardiovascular diseases has been elucidated over the last few years, including the long QT syndromes, hypertrophic cardiomyopathy and dilated cardiomyopathy. While genetic heterogeneity has been demonstrated in most of these diseases, a pattern has emerged, specifically that genes encoding proteins with similar functions or involved in the same pathway are responsible for a particular disease or syndrome. Based on this observation we proposed the 'final common pathway' hypothesis. In the case of the arrhythmogenic disorders, the long QT syndromes and Brugada syndrome, mutations have been described in a number of ion channel proteins, including cardiac potassium (KVLQT1, HERG and minK) and sodium (SCN5A) channels. Thus, using the 'final common pathway' hypothesis we have proposed these diseases to be 'ion channelopathies'. Hypertrophic cardiomyopathy appears to be a disease of the sarcomere ('sarcomyopathy') since all the disease-causing mutations have been identified in the gene encoding many of the sarcomeric proteins, including β-myosin heavy chain, α-tropomyosin, troponin I and troponin T, as well as in actin, close to the β-myosin heavy chain binding site. The genes responsible for familial dilated cardiomyopathy have been less well characterized. For X-linked dilated cardiomyopathy, mutations in the dystrophin and G4.5 genes have been reported. In addition, mutations in actin (close to the dystrophin binding domain) and desmin, a component of the intermediate filaments, have been reported. However, the genes at a further 6 loci associated with autosomal dominant dilated cardiomyopathy (associated with conduction disease in 2 cases) remain unidentified. Due to the mutations in dystrophin, actin and desmin, we have proposed that dilated cardiomyopathy is a 'cytoskeletalopathy', and we are currently investigating the involvement of these genes in patients.

Original languageEnglish (US)
Pages (from-to)168-175
Number of pages8
JournalHerz
Volume25
Issue number3
DOIs
StatePublished - May 1 2000
Externally publishedYes

Fingerprint

Cytoskeletal Proteins
Dilated Cardiomyopathy
Cardiovascular Diseases
Dystrophin
Mutation
Actins
Long QT Syndrome
Desmin
Myosin Heavy Chains
Genes
Hypertrophic Cardiomyopathy
Channelopathies
Brugada Syndrome
Mink
Sarcomeres
Tropomyosin
Troponin T
Proteins
Troponin I
Genetic Heterogeneity

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

The 'final common pathway' hypothesis and inherited cardiovascular disease : The role of cytoskeletal proteins in dilated cardiomyopathy. / Bowles, Neil E.; Bowles, Karla R.; Towbin, Jeffrey.

In: Herz, Vol. 25, No. 3, 01.05.2000, p. 168-175.

Research output: Contribution to journalArticle

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