Peter J Schwartz1,2, Cristina Moreno3,4, Maria-Christina Kotta2, Matteo Pedrazzini2, Lia Crotti1,2,5,6, Federica Dagradi1, Silvia Castelletti1, Kristina H Haugaa7,8, Isabelle Denjoy9, Maria A Shkolnikova10, Paul A Brink11, Marshall J Heradien11, Sandrine R M Seyen3, Roel L H M G Spätjens3, Carla Spazzolini1, Paul G A Volders3. 1. Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Via Pier Lombardo, 22, 20135 Milan, Italy. 2. Istituto Auxologico Italiano, IRCCS, Laboratory of Cardiovascular Genetics, via Zucchi 18, 20095 Cusano Milanino, MI, Italy. 3. Department of Cardiology, CARIM, Maastricht University Medical Center, PO Box 5800, 6202 Maastricht, The Netherlands. 4. Molecular Neurophysiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Dr., Bethesda, MD 20892-3701, USA. 5. Department of Cardiovascular, Neural and Metabolic Sciences, Istituto Auxologico Italiano, IRCCS, San Luca Hospital, Piazzale Brescia 20, 20149 Milan, Italy. 6. Department of Medicine and Surgery, University of Milano-Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milano, Italy. 7. ProCardio center for innovation, Department of Cardiology, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway. 8. University of Oslo, Postboks 1171, Blindern 0318 Oslo, Norway. 9. Centre de Référence Maladies Cardiaques Héréditaires, Filière Cardiogen, Département de Rythmologie, Groupe Hospitalier Bichat-Claude Bernard, 46 Rue Henri -Huchard, 75877 PARIS Cedex 18, France. 10. Pirogov Russian National Research Medical University, Research and Clinical Institute for Pediatrics named after Academician Yuri Veltischev, Centre for Cardiac Arrhythmia, Taldomskaya 2, 125412 Moscow, Russian Federation. 11. Department of Internal Medicine, Stellenbosch University, Tygerberg 7505, South Africa.
Abstract
AIMS: Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs 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 < 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 IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs 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 < 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 IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Steven O Marx; Junko Kurokawa; Steven Reiken; Howard Motoike; Jeanine D'Armiento; Andrew R Marks; Robert S Kass Journal: Science Date: 2002-01-18 Impact factor: 47.728
Authors: P J Schwartz; S G Priori; C Spazzolini; A J Moss; G M Vincent; C Napolitano; I Denjoy; P Guicheney; G Breithardt; M T Keating; J A Towbin; A H Beggs; P Brink; A A Wilde; L Toivonen; W Zareba; J L Robinson; K W Timothy; V Corfield; D Wattanasirichaigoon; C Corbett; W Haverkamp; E Schulze-Bahr; M H Lehmann; K Schwartz; P Coumel; R Bloise Journal: Circulation Date: 2001-01-02 Impact factor: 29.690
Authors: Lia Crotti; Carla Spazzolini; Peter J Schwartz; Wataru Shimizu; Isabelle Denjoy; Eric Schulze-Bahr; Elena V Zaklyazminskaya; Heikki Swan; Michael J Ackerman; Arthur J Moss; Arthur A M Wilde; Minoru Horie; Paul A Brink; Roberto Insolia; Gaetano M De Ferrari; Gabriele Crimi Journal: Circulation Date: 2007-11-05 Impact factor: 29.690
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Authors: W Zareba; A J Moss; P J Schwartz; G M Vincent; J L Robinson; S G Priori; J Benhorin; E H Locati; J A Towbin; M T Keating; M H Lehmann; W J Hall Journal: N Engl J Med Date: 1998-10-01 Impact factor: 91.245
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