Significant progress has been made in identifying single gene mutations responsible for causing human cardiomyopathies. Although many of these monogenic cardiomyopathies are rare, insights into pathogenesis by identification of the responsible mutations can provide clues about mechanisms in more common forms of heart disease.We have studied a group of human cardiomyopathies caused by mutations in genes encoding proteins that function as linkers in cell-cell adhesion junctions. These heart diseases, which we have termed cell-cell junction cardiomyopathies, are caused by mutations in intracellular proteins that link adhesion molecules at adherens junctions and desmosomes to the myocyte cytoskeleton. Among the genes implicated in these diseases are those encoding desmoplakin, plakoglobin, and plakophilin-2. These mutations have both dominant and recessive patterns of inheritance and are associated with clinical phenotypes of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) or dilat cardiomyopathy (DCM), with or without hair and skin abnormalities [1].Common features of the cell-cell junction cardiomyopathies are a high incidence of syncope, ventricular arrhythmias, and sudden cardiac death. This observation suggests that alterations in intercellular adhesion caused by defects in cell-cell mechanical junctions may create anatomic substrates that are particularly conducive to the development of lethal ventricular arrhythmias. Our work in this area has focused on the hypothesis that defective mechanical linkage in the cell-cell junction cardiomyopathies causes remodeling of gap junctions, which, in turn, can give rise to conduction abnormalities that may contribute to the high incidence of sudden death in these patients.


Junction Protein Intercalate Disk Palmoplantar Keratoderma Woolly Hair Naxos Disease 
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© Springer-Verlag Italia 2007

Authors and Affiliations

  • Jeffrey E. Saffitz
    • 1
  1. 1.Department of Pathology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

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