Key result
Co-expression of the A561V mutant with wild-type HERG reduced wild-type protein abundance due to decreased synthesis and increased turnover, establishing protein misfolding as a dominant effect mechanism.
Why the study?
Does the A561V mutation reduce wild-type HERG expression in mammalian cells?
Population
Mammalian cells
Comparison
Co-expression of wild-type HERG with the A561V… vs Various cDNA ratios of mutant to wild-type HERG
Design
Preclinical
Authors
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Highlights misfolding-driven dominant-negative HERG effects in LQT2; leaves open whether folding modulators offer clinical benefit.
Does the A561V mutation reduce wild-type HERG expression in mammalian cells?
The dominant negative effect of the A561V mutation in LQT2 results from assembly of wild-type subunits with mutant early in production, leading to rapid recognition and proteolysis.
Kagan et al. (2000) studied Long QT syndrome (LQT2). Co-expression of wild-type HERG with the A561V mutant vs. Wild-type HERG alone was evaluated on HERG K(+) current densities and full-length wild-type HERG protein expression. Co-expression of the A561V mutant with wild-type HERG reduced wild-type protein abundance due to decreased synthesis and increased turnover, establishing protein misfolding as a dominant effect mechanism.
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