Predicting changes to INa from missense mutations in human SCN5A

Scientific Reports
Michael ClerxPaul G A Volders

Abstract

Mutations in SCN5A can alter the cardiac sodium current INa and increase the risk of potentially lethal conditions such as Brugada and long-QT syndromes. The relation between mutations and their clinical phenotypes is complex, and systems to predict clinical severity of unclassified SCN5A variants perform poorly. We investigated if instead we could predict changes to INa, leaving the link from INa to clinical phenotype for mechanistic simulation studies. An exhaustive list of nonsynonymous missense mutations and resulting changes to INa was compiled. We then applied machine-learning methods to this dataset, and found that changes to INa could be predicted with higher sensitivity and specificity than most existing predictors of clinical significance. The substituted residues' location on the protein correlated with channel function and strongly contributed to predictions, while conservedness and physico-chemical properties did not. However, predictions were not sufficiently accurate to form a basis for mechanistic studies. These results show that changes to INa, the mechanism through which SCN5A mutations create cardiac risk, are already difficult to predict using purely in-silico methods. This partly explains the limited succes...Continue Reading

References

Jun 5, 1992·Science·G H GonnetS A Benner
Nov 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·J J Rosenthal, W F Gilly
Jul 2, 1998·Biophysical Journal·C N Pace, J M Scholtz
Jan 11, 2000·Journal of Chemical Information and Computer Sciences·B D Silverman
Nov 28, 2002·Physiological Genomics·Bin YeJonathan C Makielski
May 16, 2003·Clinical Chemistry and Laboratory Medicine : CCLM·Carlo NapolitanoSilvia G Priori
Jan 28, 2004·The Journal of General Physiology·Howard K MotoikeRobert S Kass
Feb 3, 2004·Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology·E MoricT Wilczok
Mar 27, 2004·Physiological Reviews·André G Kléber, Yoram Rudy
May 29, 2007·Nucleic Acids Research·Yana Bromberg, Burkhard Rost
Sep 12, 2007·Bioinformatics·M A LarkinD G Higgins
May 6, 2008·American Journal of Physiology. Heart and Circulatory Physiology·Markéta BébarováPaul G A Volders
Nov 26, 2008·Progress in Biophysics and Molecular Biology·Thomas Zimmer, Ralf Surber
Jul 17, 2009·Human Mutation·Paula L HedleyMichael Christiansen
Sep 12, 2009·Journal of Molecular and Cellular Cardiology·Hugues Abriel
Feb 5, 2010·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Jamie D KapplingerMichael J Ackerman
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Sep 9, 2010·PLoS Computational Biology·Amrita X Sarkar, Eric A Sobie
Jun 29, 2012·Cardiovascular Research·Jérôme ClatotNathalie Neyroud
Nov 17, 2012·Journal of the American College of Cardiology·Ryan HoefenCoeli M Lopes
Jun 19, 2013·American Journal of Physiology. Heart and Circulatory Physiology·Anthony W HerrenEleonora Grandi
Aug 29, 2014·Journal of Medical Genetics·Andreas BrunklausSameer M Zuberi
Mar 6, 2015·Frontiers in Physiology·Mohamed-Yassine Amarouch, Hugues Abriel
Nov 18, 2015·Circulation·Rahul C Deo
Oct 22, 2016·Progress in Biophysics and Molecular Biology·Igor N BerezovskyZejun Zheng

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Citations

Feb 23, 2020·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Dominic G WhittakerGary R Mirams
May 22, 2020·Journal of Cardiovascular Electrophysiology·Tadashi NakajimaMasahiko Kurabayashi
May 26, 2020·Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences·Chon Lok LeiGary R Mirams
Aug 18, 2020·Science Translational Medicine·Henrike O HeyneMark J Daly
Feb 19, 2021·Circulation Research·Natalia A TrayanovaJulie K Shade
Feb 21, 2021·Journal of Electrocardiology·Takashi SasakiMasahiko Kurabayashi
Apr 3, 2021·American Journal of Human Genetics·Gregory McInnesRuss B Altman
Jul 28, 2021·Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology·Katja E OdeningJordi Heijman
Aug 2, 2021·The Canadian Journal of Cardiology·Ben NgVijay S Chauhan

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Datasets Mentioned

BETA
AC137587
AY148488
M77235

Methods Mentioned

BETA
transgenic

Software Mentioned

SNPs
SQLite
Clustal
PolyPhen
SNAP
GO
Weka
SIFT
Python
PROVEAN

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