scholarly journals Structural Modelling of KCNQ1 and KCNH2 Double Mutant Proteins, Identified in Two Severe Long QT Syndrome Cases, Reveals New Insights into Cardiac Channelopathies

2021 ◽  
Vol 22 (23) ◽  
pp. 12861
Author(s):  
William A. Agudelo ◽  
Sebastian Ramiro Gil-Quiñones ◽  
Alejandra Fonseca ◽  
Alvaro Arenas ◽  
Laura Castro ◽  
...  

Congenital long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of the QT interval and T-wave abnormalities, caused, in most cases, by mutations in KCNQ1, KCNH2, and SCN5A. Although the predominant pattern of LQTS inheritance is autosomal dominant, compound heterozygous mutations in genes encoding potassium channels have been reported, often with early disease onset and more severe phenotypes. Since the molecular mechanisms underlying severe phenotypes in carriers of compound heterozygous mutations are unknown, it is possible that these compound mutations lead to synergistic or additive alterations to channel structure and function. In this study, all-atom molecular dynamic simulations of KCNQ1 and hERG channels were carried out, including wild-type and channels with compound mutations found in two patients with severe LQTS phenotypes and limited family history of the disease. Because channels can likely incorporate different subunit combinations from different alleles, there are multiple possible configurations of ion channels in LQTS patients. This analysis allowed us to establish the structural impact of different configurations of mutant channels in the activated/open state. Our data suggest that channels with these mutations show moderate changes in folding energy (in most cases of stabilizing character) and changes in channel mobility and volume, differentiating them from each other and from WT. This would indicate possible alterations in K+ ion flow. Hetero-tetrameric mutant channels showed intermediate structural and volume alterations vis-à-vis homo-tetrameric channels. These findings support the hypothesis that hetero-tetrameric channels in patients with compound heterozygous mutations do not necessarily lead to synergistic structural alterations.

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Sara I Liin ◽  
Johan E Larsson ◽  
Rene Barro-Soria ◽  
Bo Hjorth Bentzen ◽  
H Peter Larsson

About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.


Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1144
Author(s):  
Makoto Ono ◽  
Don E. Burgess ◽  
Elizabeth A. Schroder ◽  
Claude S. Elayi ◽  
Corey L. Anderson ◽  
...  

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2.


FEBS Letters ◽  
1998 ◽  
Vol 423 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Naomasa Makita ◽  
Nobumasa Shirai ◽  
Masato Nagashima ◽  
Rumiko Matsuoka ◽  
Yoichi Yamada ◽  
...  

2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Ian W. Glaaser ◽  
Jeremiah D. Osteen ◽  
Akil Puckerin ◽  
Kevin J. Sampson ◽  
Xiangshu Jin ◽  
...  

2006 ◽  
Vol 38 (4) ◽  
pp. 294-304 ◽  
Author(s):  
Heidi Fodstad ◽  
Saïd Bendahhou ◽  
Jean‐Sébastien Rougier ◽  
Päivi J. Laitinen‐Forsblom ◽  
Jacques Barhanin ◽  
...  

2021 ◽  
Vol 22 (15) ◽  
pp. 8090
Author(s):  
Daniela Baracaldo-Santamaría ◽  
Kevin Llinás-Caballero ◽  
Julián Miguel Corso-Ramirez ◽  
Carlos Martín Restrepo ◽  
Camilo Alberto Dominguez-Dominguez ◽  
...  

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.


2006 ◽  
Vol 2 (1) ◽  
pp. 81-94 ◽  
Author(s):  
Phillip J Stansfeld ◽  
Michael J Sutcliffe ◽  
John S Mitcheson

Sign in / Sign up

Export Citation Format

Share Document