Heart and Vessels

, Volume 34, Issue 1, pp 177–188 | Cite as

A novel mutation KCNQ1p.Thr312del is responsible for long QT syndrome type 1

  • Xiao-Meng Chen
  • Kai Guo
  • Hong Li
  • Qiu-Fen Lu
  • Chao Yang
  • Ying Yu
  • Jian-Wen Hou
  • Yu-Dong Fei
  • Jian Sun
  • Jun Wang
  • Yi-Xue LiEmail author
  • Yi-Gang LiEmail author
Original Article


Patients with high-risk long QT syndrome (LQTS) mutations may experience life-threatening cardiac events. The present study sought to characterize a novel pathogenic mutation, KCNQ1p.Thr312del, in a Chinese LQT1 family. Clinical and genetic analyses were performed to identify this novel causative gene mutation in this LQTS family. Autosomal dominant inheritance of KCNQ1p.T312del was demonstrated in the three-generation pedigree. All mutation carriers presented with prolonged QT intervals and experienced recurrent syncope during exercise or emotional stress. The functional consequences of the mutant channel were investigated by computer homology modeling as well as whole-cell patch-clamp, western-blot and co-immunoprecipitation techniques using transfected mammalian cells. T312 is in the selectivity filter (SF) of the pore region of the KCNQ1-encoded channel. Homology modeling suggested that secondary structure was altered in the mutant SF compared with the wild-type (WT) SF. There were no significant differences in Kv7.1 expression, membrane trafficking or physical interactions with KCNE1-encoded subunits between the WT and mutant transfected channels. However, the KCNQ1p.T312del channels expressed in transfected cells were non-functional in the absence or presence of auxiliary KCNE1-subunits. Dominant-negative suppression of current density and decelerated activation kinetics were observed in cells expressing KCNQ1WT and KCNQ1p.T312del combined with KCNE1 (KCNQ1WT/p.T312del + KCNE1 channels). Those electrophysiological characteristics underlie the pathogenesis of this novel mutation and also suggest a high risk of cardiac events in patients carrying KCNQ1p.T312del. Although protein kinase A-dependent current increase was preserved, a significant suppression of rate-dependent current facilitation was noted in the KCNQ1WT/p.T312del + KCNE1 channels compared to the WT channels during 1- and 2-Hz stimulation, which was consistent with the patients’ phenotype being triggered by exercise. Overall, KCNQ1p.Thr312del induces a loss of function in channel electrophysiology, and it is a high-risk mutation responsible for LQT1.


Electrophysiology Long QT syndrome KCNQ1 Selectivity filter 



This work was supported by National Natural Science Foundation of China (no. 81270258), the State Key Program of National Natural Science Foundation of China (no. 81530015), Shanghai City Committee of Science and Technology Research Projects (nos. 12411951900, 13140903801, and 14441902502) and Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine (BXJ201427).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

380_2018_1223_MOESM1_ESM.pdf (1005 kb)
Supplementary material 1 (PDF 1004 kb)


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Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Xiao-Meng Chen
    • 1
  • Kai Guo
    • 1
  • Hong Li
    • 2
  • Qiu-Fen Lu
    • 1
  • Chao Yang
    • 3
  • Ying Yu
    • 1
  • Jian-Wen Hou
    • 1
  • Yu-Dong Fei
    • 1
  • Jian Sun
    • 1
  • Jun Wang
    • 1
  • Yi-Xue Li
    • 2
    Email author
  • Yi-Gang Li
    • 1
    Email author
  1. 1.Department of Cardiology, School of Medicine, Xinhua HospitalShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  3. 3.Xinhua Translational Institute for Cancer Pain, School of Medicine, Xinhua Hospital (Chongming)Shanghai Jiao Tong UniversityShanghaiChina

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