A hERG mutation E1039X produced a synergistic lesion on I(Ks) together with KCNQ1-R174C mutation in a LQTS family with three compound mutations.

Congenital long QT syndrome (LQTS) caused by compound mutations is usually associated with more severe clinical phenotypes. We identified a LQTS family harboring three compound mutations in different genes (KCNQ1-R174C, hERG-E1039X and SCN5A-E428K). KCNQ1-R174C, hERG-E1039X and SCN5A-E428K mutations and/or relevant wild-type (WT) cDNAs were respectively expressed in mammalian cells. I(Ks)-like, I(Kr)-like, I(Na)-like currents and the functional interaction between KCNQ1-R174C and hERG-E1039X channels were studied using patch-clamp and immunocytochemistry techniques. (1) Expression of KCNQ1-R174C alone showed no I(Ks). Co-expression of KCNQ1-WT + KCNQ1-R174C caused a loss-of-function in I(Ks) and blunted the activation of I(Ks) in response to isoproterenol. (2) Expression of hERG-E1039X alone and co-expression of hERG-WT + hERG-E1039X negatively shifted inactivation curves and decelerated the recovery time from inactivation. (3) Expression of SCN5A-E428K increased peak I(Na), but had no effect on late I(Na). (4) I(Ks) and I(Kr) interact, and hERG-E1039X caused a loss-of-function in I(Ks). (5) Immunocytochemical studies indicated that KCNQ1-R174C is trafficking defective and hERG-E1039X is defective in biosynthesis/degradation, but the abnormities were rescued by co-expression with WT. Thus, KCNQ1-R174C and hERG-E1039X disrupted I(Ks) and I(Kr) functions, respectively. The synergistic lesion, caused by KCNQ1-R174C and hERG-E1039X in I(Ks), is very likely why patients showed more severe phenotypes in the compound mutation case.