Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome

Andersen-Tawil Syndrome (ATS) is a rare disease defined by the association of cardiac arrhythmias, periodic paralysis and dysmorphic features, and is caused by KCNJ2 loss-of-function mutations. However, when extracardiac symptoms are atypical or absent, the patient can be diagnosed with Catecholamin...

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Autores principales:	Pauline Le Tanno, Mathilde Folacci, Jean Revilloud, Laurence Faivre, Gabriel Laurent, Lucile Pinson, Pascal Amedro, Gilles Millat, Alexandre Janin, Michel Vivaudou, Nathalie Roux-Buisson, Julien Fauré
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	catecholaminergic polymorphic ventricular tachycardia Andersen-Tawil syndrome Kir2.1 channel Pierre Robin sequence functionnal characterization KCNJ2 variants Genetics QH426-470
Acceso en línea:	https://doaj.org/article/1eea676b9315439d98a82f282c9786d4
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spelling	oai:doaj.org-article:1eea676b9315439d98a82f282c9786d42021-12-01T01:12:23ZCharacterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome1664-802110.3389/fgene.2021.773177https://doaj.org/article/1eea676b9315439d98a82f282c9786d42021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.773177/fullhttps://doaj.org/toc/1664-8021Andersen-Tawil Syndrome (ATS) is a rare disease defined by the association of cardiac arrhythmias, periodic paralysis and dysmorphic features, and is caused by KCNJ2 loss-of-function mutations. However, when extracardiac symptoms are atypical or absent, the patient can be diagnosed with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a rare arrhythmia at high risk of sudden death, mostly due to RYR2 mutations. The identification of KCNJ2 variants in CPVT suspicion is very rare but important because beta blockers, the cornerstone of CPVT therapy, could be less efficient. We report here the cases of two patients addressed for CPVT-like phenotypes. Genetic investigations led to the identification of p. Arg82Trp and p. Pro186Gln de novo variants in the KCNJ2 gene. Functional studies showed that both variants forms of Kir2.1 monomers act as dominant negative and drastically reduced the activity of the tetrameric channel. We characterize here a new pathogenic variant (p.Pro186Gln) of KCNJ2 gene and highlight the interest of accurate cardiologic evaluation and of attention to extracardiac signs to distinguish CPVT from atypical ATS, and guide therapeutic decisions. We also confirm that the KCNJ2 gene must be investigated during CPVT molecular analysis.Pauline Le TannoMathilde FolacciJean RevilloudLaurence FaivreGabriel LaurentLucile PinsonLucile PinsonLucile PinsonPascal AmedroGilles MillatAlexandre JaninMichel VivaudouNathalie Roux-BuissonJulien FauréFrontiers Media S.A.articlecatecholaminergic polymorphic ventricular tachycardiaAndersen-Tawil syndromeKir2.1 channelPierre Robin sequencefunctionnal characterizationKCNJ2 variantsGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	catecholaminergic polymorphic ventricular tachycardia Andersen-Tawil syndrome Kir2.1 channel Pierre Robin sequence functionnal characterization KCNJ2 variants Genetics QH426-470
spellingShingle	catecholaminergic polymorphic ventricular tachycardia Andersen-Tawil syndrome Kir2.1 channel Pierre Robin sequence functionnal characterization KCNJ2 variants Genetics QH426-470 Pauline Le Tanno Mathilde Folacci Jean Revilloud Laurence Faivre Gabriel Laurent Lucile Pinson Lucile Pinson Lucile Pinson Pascal Amedro Gilles Millat Alexandre Janin Michel Vivaudou Nathalie Roux-Buisson Julien Fauré Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome
description	Andersen-Tawil Syndrome (ATS) is a rare disease defined by the association of cardiac arrhythmias, periodic paralysis and dysmorphic features, and is caused by KCNJ2 loss-of-function mutations. However, when extracardiac symptoms are atypical or absent, the patient can be diagnosed with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a rare arrhythmia at high risk of sudden death, mostly due to RYR2 mutations. The identification of KCNJ2 variants in CPVT suspicion is very rare but important because beta blockers, the cornerstone of CPVT therapy, could be less efficient. We report here the cases of two patients addressed for CPVT-like phenotypes. Genetic investigations led to the identification of p. Arg82Trp and p. Pro186Gln de novo variants in the KCNJ2 gene. Functional studies showed that both variants forms of Kir2.1 monomers act as dominant negative and drastically reduced the activity of the tetrameric channel. We characterize here a new pathogenic variant (p.Pro186Gln) of KCNJ2 gene and highlight the interest of accurate cardiologic evaluation and of attention to extracardiac signs to distinguish CPVT from atypical ATS, and guide therapeutic decisions. We also confirm that the KCNJ2 gene must be investigated during CPVT molecular analysis.
format	article
author	Pauline Le Tanno Mathilde Folacci Jean Revilloud Laurence Faivre Gabriel Laurent Lucile Pinson Lucile Pinson Lucile Pinson Pascal Amedro Gilles Millat Alexandre Janin Michel Vivaudou Nathalie Roux-Buisson Julien Fauré
author_facet	Pauline Le Tanno Mathilde Folacci Jean Revilloud Laurence Faivre Gabriel Laurent Lucile Pinson Lucile Pinson Lucile Pinson Pascal Amedro Gilles Millat Alexandre Janin Michel Vivaudou Nathalie Roux-Buisson Julien Fauré
author_sort	Pauline Le Tanno
title	Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome
title_short	Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome
title_full	Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome
title_fullStr	Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome
title_full_unstemmed	Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome
title_sort	characterization of loss-of-function kcnj2 mutations in atypical andersen tawil syndrome
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/1eea676b9315439d98a82f282c9786d4
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Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome

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