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

• Wu, Jie

  Department of Pharmacology, Medical School of Xi’an Jiaotong University・Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science・Department of Physiology, Shiga University of Medical Science

• Mizusawa, Yuka

  Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science

• Ohno, Seiko

  Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science

• Ding, Wei-Guang

  Department of Physiology, Shiga University of Medical Science

• Higaki, Takashi

  Department of Pediatrics, Ehime University School of Medicine

• Wang, Qi

  Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science

• Kohjitani, Hirohiko

  Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine

• Makiyama, Takeru

  Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine

• Itoh, Hideki

  Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science

• Toyoda, Futoshi

  Department of Physiology, Shiga University of Medical Science

• James, Andrew F.

  School of Physiology, Pharmacology and Neuroscience, University of Bristol

• Hancox, Jules C.

  School of Physiology, Pharmacology and Neuroscience, University of Bristol

• Matsuura, Hiroshi

  Department of Physiology, Shiga University of Medical Science

• Horie, Minoru

  Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science

Bibliographic Information

Other Title

• A hERG-E1039X mutation and KCNQ1-R174C mutation produced a synergistic lesion on cardiac IKs channel in a compound LQTS family

Abstract

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. IKs-like, IKr-like, INa-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 IKs. Co-expression of KCNQ1-WT + KCNQ1-R174C caused a loss-of-function in IKs and blunted the activation of IKs 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 INa, but had no effect on late INa. (4) IKs and IKr interact, and hERG-E1039X caused a loss-of-function in IKs. (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 IKs and IKr functions, respectively. The synergistic lesion, caused by KCNQ1-R174C and hERG-E1039X in IKs, is very likely why patients showed more severe phenotypes in the compound mutation case.

Journal

• Scientific Reports

  Scientific Reports 8 3129-, 2018-12

  Springer Nature

Keywords

• Multidisciplinary

Details

• CRID: 1050001338207718144
• NII Article ID: 120006529715
• ISSN: 20452322
• DOI: 10.1038/s41598-018-21442-6
• HANDLE: 2433/234672
• Web Site: https://www.nature.com/articles/s41598-018-21442-6
• Web Site: https://www.nature.com/articles/s41598-018-21442-6.pdf
• Text Lang: en
• Article Type: journal article
• Data Source:
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  • Crossref
  • CiNii Articles
  • KAKEN