Conclusions

We have proposed a unified hypothesis that links contractile and electrical dysfunction in the cell-cell junction cardiomyopathies. It is based on the premise that the extent to which cardiac myocytes are coupled mechanically at cell-cell adhesion junctions is a key determinant of the extent to which they can be coupled electrically at gap junctions. Our observations in several human cardiomyopathies indicate that genetic defects in linker proteins such as desmoplakin and plakoglobin can create anatomic substrates of sudden death by remodeling gap junctions. Molecular mechanisms responsible for gap junction remodeling in the cell-cell junction cardiomyopathies are unknown. One possi bility is that rates of Cx43 synthesis and degradation are unaffected but connexin molecules are unable to assemble properly in gap junctions. It must also be considered, however, that Cx43 gene expression may be altered in the cell-cell junction cardiomyopathies. Plakoglobin and other members of the catenin family fulfill both structural and nuclear signaling roles [16]. Disease-related mutations may shift the relative proportions of these proteins within junctional and cytosolic pools, which, in turn, could affect nuclear signaling mediated by plakoglobin, or ^-catenin or other related proteins. If, for example, ^-catenin substitutes for mutant plakoglobin within cell-cell junctions, then the resultant decrease in the cytosolic pool of ^-catenin could lead to diminished expression of Cx43 and other proteins under the control of ^-catenin signaling. Thus, it is possible and perhaps even likely that both altered mechanical integrity and altered nuclear signaling underlie the pathogenesis of contractile and electrical dysfunction in heart muscle diseases caused by mutations in cell-cell junction proteins.

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