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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.

A hERG mutation E1039X produced a synergistic lesion on IKs together with KCNQ1-R174C mutation in a LQTS family with three compound mutations