Clinical, genetic and functional analysis of R562S-Kv7.1
mutation associated with long QT syndrome type 1

a 2021

Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1

ŠVECOVÁ, Olga; Roman KULA; Larisa CHMELÍKOVÁ; Jan HOŠEK; Iva SYNKOVÁ et al.

Základní údaje

Originální název

Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1

Autoři

ŠVECOVÁ, Olga ; Roman KULA ; Larisa CHMELÍKOVÁ; Jan HOŠEK; Iva SYNKOVÁ; Tomáš NOVOTNÝ a Markéta BÉBAROVÁ

Vydání

EHRA-EWGCCE 2021, 2021

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

30201 Cardiac and Cardiovascular systems

Stát vydavatele

Španělsko

Utajení

není předmětem státního či obchodního tajemství

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/21:00134967

Organizační jednotka

Lékařská fakulta

ISSN

DOI

https://doi.org/10.1093/europace/euab116.560

Klíčová slova česky

mutace R562S; syndrom dlouhého intervalu QT; dysfunkce

Klíčová slova anglicky

R562S mutation; long QT syndrome; dysfunction

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 18. 3. 2025 09:37, doc. MUDr. Markéta Bébarová, Ph.D.

Anotace

V originále

Introduction: Loss-of-function variants of the KCNQ1 gene are associated with life-threatening arrhythmogenic long QT syndrome type 1 (LQT1). This gene encodes structure of the slow delayed rectifier potassium channel (IKs). Some functional characteristics of the C-terminal KCNQ1 variant c.1686G>C (p.R562S) have been recently described (1). However, accumulation of the current under beta-adrenergic stimulation, essential for shortening the action potential duration during exercise, have not been tested. Purpose: The aim of this study was to analyse clinical and genetic characteristics of the R562S variant in our patients and to investigate impact of the variant on IKs channel function with a special focus on reactivity of the channels on beta-adrenergic stimulation. Methods: The clinical diagnosis was established according to ESC Guidelines including QTc analysis at rest and after exercise. The molecular genetics diagnostics followed according to current practices (the massive parallel sequencing since 2016). The biophysical analysis was performed on Chinese hamster ovary cells (CHO) by the whole cell patch clamp technique at 37 °C. CHO cells were transiently transfected with wild type (WT) and/or R562S human IKs channels (KCNQ1/KCNE1/Yotiao, 1:2:4). Cyclic adenosine monophosphate (cAMP, 200 µM) and okadaic acid (OA, 0.2 µM) in the pipette solution were used to simulate the beta-adrenergic stimulation. In the confocal microscopy experiments, expression of Yotiao was omitted and GFP-tagged KCNQ1 was used. Results: The variant R562S-Kv7.1 has been identified in 7 heterozygous carriers from 3 putatively unrelated families in the Czech Republic. The genotype was associated with long QT syndrome phenotype (prolonged QTc, symptoms including syncopes and aborted cardiac arrest) in some of the carriers. The basic functional analysis proved that both homozygous and heterozygous R562S channels are expressed on the cell membrane (confocal microscopy) and carry IKs (whole cell patch clamp) which agrees with the recently published data on this variant. Importantly, reactivity on beta-adrenergic stimulation was absent in both homozygous and heterozygous R562S channels (n = 14 and 8, respectively), but present in the wild-type channels (increase by 51.4 ± 11.1 % at 120-s cAMP/OA diffusion; n = 12). Conclusions: The R562S-Kv7.1 variant may be a founder LQT1 variant in our region which will be further investigated in the future. This variant impairs response of IKs channel to beta-adrenergic stimulation. Absence of this essential regulation may considerably aggravate the channel dysfunction and, thus, may result in life-threatening arrhythmias in R562S carriers during exercise. (1) Liu Z, Zheng R, Grushko MJ, Uversky VN, McDonald TV. Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes. Can J Cardiol 2018;34:1174-1184.

Návaznosti

MUNI/A/1246/2020, interní kód MU

Název: Kardiovaskulární systém: od iontového kanálu k celotělovému modelu (Akronym: KAVASYKAMO)

Investor: Masarykova univerzita, Kardiovaskulární systém: od iontového kanálu k celotělovému modelu

Citovat

ŠVECOVÁ, Olga; Roman KULA; Larisa CHMELÍKOVÁ; Jan HOŠEK; Iva SYNKOVÁ; Tomáš NOVOTNÝ a Markéta BÉBAROVÁ. Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1. In EHRA-EWGCCE 2021. 2021. ISSN 1532-2092. Dostupné z: https://doi.org/10.1093/europace/euab116.560.

@proceedings{1798482,
   author = {Švecová, Olga and Kula, Roman and Chmelíková, Larisa and Hošek, Jan and Synková, Iva and Novotný, Tomáš and Bébarová, Markéta},
   booktitle = {EHRA-EWGCCE 2021},
   doi = {https://doi.org/10.1093/europace/euab116.560},
   keywords = {R562S mutation; long QT syndrome; dysfunction},
   language = {eng},
   title = {Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1},
   year = {2021}
}

TY  - CONF
ID  - 1798482
AU  - Švecová, Olga - Kula, Roman - Chmelíková, Larisa - Hošek, Jan - Synková, Iva - Novotný, Tomáš - Bébarová, Markéta
PY  - 2021
TI  - Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1
KW  - R562S mutation
KW  - long QT syndrome
KW  - dysfunction
N2  - Introduction: Loss-of-function variants of the KCNQ1 gene are associated with life-threatening arrhythmogenic long QT syndrome type 1 (LQT1). This gene encodes structure of the slow delayed rectifier potassium channel (IKs). Some functional characteristics of the C-terminal KCNQ1 variant c.1686G>C (p.R562S) have been recently described (1). However, accumulation of the current under beta-adrenergic stimulation, essential for shortening the action potential duration during exercise, have not been tested. Purpose: The aim of this study was to analyse clinical and genetic characteristics of the R562S variant in our patients and to investigate impact of the variant on IKs channel function with a special focus on reactivity of the channels on beta-adrenergic stimulation. Methods: The clinical diagnosis was established according to ESC Guidelines including QTc analysis at rest and after exercise. The molecular genetics diagnostics followed according to current practices (the massive parallel sequencing since 2016). The biophysical analysis was performed on Chinese hamster ovary cells (CHO) by the whole cell patch clamp technique at 37 °C. CHO cells were transiently transfected with wild type (WT) and/or R562S human IKs channels (KCNQ1/KCNE1/Yotiao, 1:2:4). Cyclic adenosine monophosphate (cAMP, 200 µM) and okadaic acid (OA, 0.2 µM) in the pipette solution were used to simulate the beta-adrenergic stimulation. In the confocal microscopy experiments, expression of Yotiao was omitted and GFP-tagged KCNQ1 was used. Results: The variant R562S-Kv7.1 has been identified in 7 heterozygous carriers from 3 putatively unrelated families in the Czech Republic. The genotype was associated with long QT syndrome phenotype (prolonged QTc, symptoms including syncopes and aborted cardiac arrest) in some of the carriers. The basic functional analysis proved that both homozygous and heterozygous R562S channels are expressed on the cell membrane (confocal microscopy) and carry IKs (whole cell patch clamp) which agrees with the recently published data on this variant. Importantly, reactivity on beta-adrenergic stimulation was absent in both homozygous and heterozygous R562S channels (n = 14 and 8, respectively), but present in the wild-type channels (increase by 51.4 ± 11.1 % at 120-s cAMP/OA diffusion; n = 12). Conclusions: The R562S-Kv7.1 variant may be a founder LQT1 variant in our region which will be further investigated in the future. This variant impairs response of IKs channel to beta-adrenergic stimulation. Absence of this essential regulation may considerably aggravate the channel dysfunction and, thus, may result in life-threatening arrhythmias in R562S carriers during exercise. (1) Liu Z, Zheng R, Grushko MJ, Uversky VN, McDonald TV. Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes. Can J Cardiol 2018;34:1174-1184.
ER  -

ŠVECOVÁ, Olga; Roman KULA; Larisa CHMELÍKOVÁ; Jan HOŠEK; Iva SYNKOVÁ; Tomáš NOVOTNÝ a Markéta BÉBAROVÁ. Clinical, genetic and functional analysis of R562S-Kv7.1 mutation associated with long QT syndrome type 1. In \textit{EHRA-EWGCCE 2021}. 2021. ISSN~1532-2092. Dostupné z: https://doi.org/10.1093/europace/euab116.560.

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