Mechanisms of disease pathogenesis in XXXX .

@entity9677 @entity71092 @entity15500 @entity45184 @entity71095 @entity71094 @entity1162 @entity71093
@entity15500 associates with the pore-forming alpha-subunit @entity9677 to generate the slow (I(Ks)) current in cardiac myocytes. Mutations in either @entity9677 or @entity15500 can alter the biophysical properties of I(Ks) and mutations in @entity15500 underlie cases of @entity1162 ( @entity1162 ). We previously investigated a mutation in @entity15500 , @entity71092 / @entity71093 , which causes severe attenuation of I(Ks). However, how @entity71092 / @entity71093 acts to disrupt I(Ks) has not been determined. In this study, we investigate and compare the effects of @entity71092 / @entity71093 with three other @entity1162 mutations ( @entity45184 , @entity71094 , and @entity71095 ) on the biophysical properties of the current, trafficking of @entity9677 , and assembly of the I(Ks) channel. @entity45184 and @entity71092 / @entity71093 produce currents that lack the kinetic behavior of I(Ks). In contrast, @entity71094 and @entity71095 both produce I(Ks)-like currents but with rightward shifted voltage dependence of activation. All of the @entity1162 mutants express protein robustly, and @entity71092 / @entity71093 and @entity71095 cause modest, but significant, defects in the trafficking of @entity9677 . Despite defects in trafficking, in the presence of @entity9677 , @entity71092 / @entity71093 and the other @entity1162 mutants are present at the plasma membrane. Interestingly, in comparison to @entity15500 and the other @entity1162 mutants, @entity71092 / @entity71093 associates only weakly with @entity9677 . In conclusion, we identify the disease mechanisms for each mutation and reveal that @entity71092 / @entity71093 causes disease through a novel mechanism that involves defective I(Ks) complex assembly.
