Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel

Over 1,500 missense variants of sodium channel hNav1.5, which are reported in the ClinVar database, are associated with cardiac diseases. For most of the variants, the clinical significance is uncertain (VUS), not provided (NP), or has conflicting interpretations of pathogenicity (CIP). Reclassifyin...

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Autores principales:	Vyacheslav S. Korkosh, Anastasia K. Zaytseva, Anna A. Kostareva, Boris S. Zhorov
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Brugada syndrome cardiac arrhythmias cryo-EM structure homology modeling intersegment contacts long QT syndrome Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/b8f1e60ccf4d4ba4a86b72243c8e92cc
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spelling	oai:doaj.org-article:b8f1e60ccf4d4ba4a86b72243c8e92cc2021-11-04T07:08:18ZIntersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel1663-981210.3389/fphar.2021.756415https://doaj.org/article/b8f1e60ccf4d4ba4a86b72243c8e92cc2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.756415/fullhttps://doaj.org/toc/1663-9812Over 1,500 missense variants of sodium channel hNav1.5, which are reported in the ClinVar database, are associated with cardiac diseases. For most of the variants, the clinical significance is uncertain (VUS), not provided (NP), or has conflicting interpretations of pathogenicity (CIP). Reclassifying these variants as pathogenic/likely pathogenic (P/LP) variants is important for diagnosing genotyped patients. In our earlier work, several bioinformatics tools and paralogue annotation method consensually predicted that 74 VUS/NP/CIP variants of 54 wild type residues (set w54) are potentially damaging variants (PDVs). Atomic mechanisms underlying dysfunction of the PDVs are unknown. Here we employed a recent cryo-EM structure of the hNav1.5 channel with likely inactivated pore domain (PD) and activated voltage-sensing domains (VSDs), and ad hoc models of the closed and open PD and resting VSDs to explore intersegment contacts of w54 residues. We found that 44 residues from set w54 contact 84 residues with 118 disease missense variants. These include 104 VUS/NP/CIP variants, most of which are associated with the loss-of-function Brugada syndrome (BrS1) or gain-of-function long QT syndrome (LQT3). Matrix representation of the PDVs and their contact variants facilitated recognition of coupled mutations associated with the same disease. In particular, BrS1-associated coupled mutations, which disturb the P-loops region with the selectivity filter slow inactivation gate, would cause the channel dysfunction. Other likely causes of the channel dysfunction include coupled BrS1-associated variants within VSDs that would destabilize their activated states and coupled LQT3-associated variants, which would stabilize the open PD or activated VSDs. Our study proposes mechanisms of channel dysfunction for scores of BrS1- and LQT3-associated variants, confirms status for 82% of PDVs, and suggests damaging status for their contact variants, which are currently categorized as VUS/NP/CIP variants.Vyacheslav S. KorkoshVyacheslav S. KorkoshAnastasia K. ZaytsevaAnastasia K. ZaytsevaAnna A. KostarevaAnna A. KostarevaBoris S. ZhorovBoris S. ZhorovBoris S. ZhorovFrontiers Media S.A.articleBrugada syndromecardiac arrhythmiascryo-EM structurehomology modelingintersegment contactslong QT syndromeTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Brugada syndrome cardiac arrhythmias cryo-EM structure homology modeling intersegment contacts long QT syndrome Therapeutics. Pharmacology RM1-950
spellingShingle	Brugada syndrome cardiac arrhythmias cryo-EM structure homology modeling intersegment contacts long QT syndrome Therapeutics. Pharmacology RM1-950 Vyacheslav S. Korkosh Vyacheslav S. Korkosh Anastasia K. Zaytseva Anastasia K. Zaytseva Anna A. Kostareva Anna A. Kostareva Boris S. Zhorov Boris S. Zhorov Boris S. Zhorov Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel
description	Over 1,500 missense variants of sodium channel hNav1.5, which are reported in the ClinVar database, are associated with cardiac diseases. For most of the variants, the clinical significance is uncertain (VUS), not provided (NP), or has conflicting interpretations of pathogenicity (CIP). Reclassifying these variants as pathogenic/likely pathogenic (P/LP) variants is important for diagnosing genotyped patients. In our earlier work, several bioinformatics tools and paralogue annotation method consensually predicted that 74 VUS/NP/CIP variants of 54 wild type residues (set w54) are potentially damaging variants (PDVs). Atomic mechanisms underlying dysfunction of the PDVs are unknown. Here we employed a recent cryo-EM structure of the hNav1.5 channel with likely inactivated pore domain (PD) and activated voltage-sensing domains (VSDs), and ad hoc models of the closed and open PD and resting VSDs to explore intersegment contacts of w54 residues. We found that 44 residues from set w54 contact 84 residues with 118 disease missense variants. These include 104 VUS/NP/CIP variants, most of which are associated with the loss-of-function Brugada syndrome (BrS1) or gain-of-function long QT syndrome (LQT3). Matrix representation of the PDVs and their contact variants facilitated recognition of coupled mutations associated with the same disease. In particular, BrS1-associated coupled mutations, which disturb the P-loops region with the selectivity filter slow inactivation gate, would cause the channel dysfunction. Other likely causes of the channel dysfunction include coupled BrS1-associated variants within VSDs that would destabilize their activated states and coupled LQT3-associated variants, which would stabilize the open PD or activated VSDs. Our study proposes mechanisms of channel dysfunction for scores of BrS1- and LQT3-associated variants, confirms status for 82% of PDVs, and suggests damaging status for their contact variants, which are currently categorized as VUS/NP/CIP variants.
format	article
author	Vyacheslav S. Korkosh Vyacheslav S. Korkosh Anastasia K. Zaytseva Anastasia K. Zaytseva Anna A. Kostareva Anna A. Kostareva Boris S. Zhorov Boris S. Zhorov Boris S. Zhorov
author_facet	Vyacheslav S. Korkosh Vyacheslav S. Korkosh Anastasia K. Zaytseva Anastasia K. Zaytseva Anna A. Kostareva Anna A. Kostareva Boris S. Zhorov Boris S. Zhorov Boris S. Zhorov
author_sort	Vyacheslav S. Korkosh
title	Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel
title_short	Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel
title_full	Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel
title_fullStr	Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel
title_full_unstemmed	Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel
title_sort	intersegment contacts of potentially damaging variants of cardiac sodium channel
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b8f1e60ccf4d4ba4a86b72243c8e92cc
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Intersegment Contacts of Potentially Damaging Variants of Cardiac Sodium Channel

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