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Mutation location and I-Ks requlation in the arrhythmic risk of long QT syndrome type 1
- Source :
- Eur Heart J, European Heart Journal, 42(46), 4743-4755. Oxford University Press
- Publication Year :
- 2021
-
Abstract
- 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.A341-neighbouring 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 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.
- Subjects :
- medicine.medical_specialty
Long QT syndrome
Romano-Ward Syndrome
Mutation, Missense
Fast Track Clinical Research
REQUIREMENT
Stimulation
VARIANTS
medicine.disease_cause
PHENOTYPE
QT interval
Sudden cardiac death
MECHANISMS
chemistry.chemical_compound
Genetic
CHANNEL
Internal medicine
medicine
Clinical endpoint
Genetics
Missense mutation
Humans
Cyclic adenosine monophosphate
Mutation
business.industry
KVLQT1
medicine.disease
GENOTYPE
DOMINANT-NEGATIVE SUPPRESSION
chemistry
KCNQ1 Potassium Channel
Cardiology
GENETIC MODIFIER
Cardiology and Cardiovascular Medicine
business
LANGE-NIELSEN-SYNDROME
Subjects
Details
- Language :
- English
- ISSN :
- 0195668X
- Volume :
- 42
- Issue :
- 46
- Database :
- OpenAIRE
- Journal :
- European Heart Journal
- Accession number :
- edsair.doi.dedup.....844d33f416c443ba9630554a3eb61ac2