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

Jie Wu, Yuka Mizusawa, Seiko Ohno, Wei Guang Ding, Takashi Higaki, Qi Wang, Hirohiko Kohjitani, Takeru Makiyama, Hideki Itoh, Futoshi Toyoda, Andrew F. James, Jules C. Hancox, Hiroshi Matsuura, Minoru Horie*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)
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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.

Original languageEnglish
Article number3129
Number of pages12
JournalScientific Reports
Issue number1
Publication statusPublished - 15 Feb 2018


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