TY - JOUR
T1 - Mutation location and I-Ks requlation in the arrhythmic risk of long QT syndrome type 1
T2 - the importance of the KCNQ1 S6 region
AU - Schwartz, Peter J
AU - Moreno, Cristina
AU - Kotta, Maria-Christina
AU - Pedrazzini, Matteo
AU - Crotti, Lia
AU - Dagradi, Federica
AU - Castelletti, Silvia
AU - Haugaa, Kristina H
AU - Denjoy, Isabelle
AU - Shkolnikova, Maria A
AU - Brink, Paul A
AU - Heradien, Marshall J
AU - Seyen, Sandrine R M
AU - Spätjens, Roel L. H.
AU - Spazzolini, Carla
AU - Volders, Paul G A
N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
PY - 2021/12/7
Y1 - 2021/12/7
N2 - Aims Mutation type, location, dominant-negative I-Ks reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I-Ks stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.Methods and results Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 +/- 33 vs. 490 +/- 44 ms) but longer than the remaining LQT1 patient population (467 +/- 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P< 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.Conclusion KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I-Ks enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I-Ks-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.[GRAPHICS].
AB - Aims Mutation type, location, dominant-negative I-Ks reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I-Ks stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.Methods and results Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 +/- 33 vs. 490 +/- 44 ms) but longer than the remaining LQT1 patient population (467 +/- 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P< 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.Conclusion KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I-Ks enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I-Ks-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.[GRAPHICS].
KW - Long QT syndrome
KW - Genetics
KW - Sudden cardiac death
KW - DOMINANT-NEGATIVE SUPPRESSION
KW - LANGE-NIELSEN-SYNDROME
KW - GENETIC MODIFIER
KW - CHANNEL
KW - KVLQT1
KW - REQUIREMENT
KW - MECHANISMS
KW - PHENOTYPE
KW - VARIANTS
KW - GENOTYPE
U2 - 10.1093/eurheartj/ehab582
DO - 10.1093/eurheartj/ehab582
M3 - Article
C2 - 34505893
SN - 0195-668X
VL - 42
SP - 4743
EP - 4755
JO - European Heart Journal
JF - European Heart Journal
IS - 46
ER -