Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2

• Verfasst von: Cordeiro, Jonathan M. [VerfasserIn]
• Verfasst von: Perez, Guillermo J. [VerfasserIn]
• Verfasst von: Schmitt, Nicole [VerfasserIn]
• Verfasst von: Pfeiffer, Ryan [VerfasserIn]
• Verfasst von: Nesterenko, Vladislav V. [VerfasserIn]
• Verfasst von: Burashnikov, Elena [VerfasserIn]
• Verfasst von: Veltmann, Christian [VerfasserIn]
• Verfasst von: Borggrefe, Martin [VerfasserIn]
• Verfasst von: Wolpert, Christian [VerfasserIn]
• Verfasst von: Schimpf, Rainer [VerfasserIn]
• Verfasst von: Antzelevitch, Charles [VerfasserIn]
• Titel: Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2
• Verf.angabe: Jonathan M. Cordeiro, Guillermo J. Perez, Nicole Schmitt, Ryan Pfeiffer, Vladislav V. Nesterenko, Elena Burashnikov, Christian Veltmann, Martin Borggrefe, Christian Wolpert, Rainer Schimpf, Charles Antzelevitch
• E-Jahr: 2010
• Jahr: 1 December 2010
• Umfang: 10 S.
• Fussnoten: Gesehen am 16.06.2023
• Titel Quelle: Enthalten in: Canadian journal of physiology and pharmacology
• Ort Quelle: Ottawa, Ont. : NRC Research Press, 1964
• Jahr Quelle: 2010
• Band/Heft Quelle: 88(2010), 12, Seite 1181-1190
• ISSN Quelle: 1205-7541
• DOI: doi:10.1139/Y10-094
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Adult
• Sach-SW: Amino Acid Sequence
• Sach-SW: Animals
• Sach-SW: Base Sequence
• Sach-SW: Cells, Cultured
• Sach-SW: CHO Cells
• Sach-SW: Cricetinae
• Sach-SW: Cricetulus
• Sach-SW: Electrocardiography
• Sach-SW: ERG1 Potassium Channel
• Sach-SW: Ether-A-Go-Go Potassium Channels
• Sach-SW: Female
• Sach-SW: Genetic Variation
• Sach-SW: Humans
• Sach-SW: KCNQ1 Potassium Channel
• Sach-SW: Long QT Syndrome
• Sach-SW: Molecular Sequence Data
• Sach-SW: Mutation
• Sach-SW: Phenotype
• Sach-SW: Polymorphism, Genetic
• K10plus-PPN: 1850471088

Abstract

Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4-V6 and LQT1 morphology in leads V1-V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared with WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = -53.1 ± 1.13 mV and -60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.