Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients
| Autor: | Hugues Abriel, Heidi Fodstad, Saïd Bendahhou, Jacques Barhanin, Heikki Swan, Laurent Schild, Kimmo Kontula, Jean-Sébastien Rougier, Päivi J. Laitinen-Forsblom |
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| Přispěvatelé: | Biomedicum Helsinki and Department of Medicine, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacology and Toxicology, Université de Lausanne (UNIL), Service of Cardiology, University Hospital, Department of Cardiology |
| Rok vydání: | 2006 |
| Předmět: |
Male
ERG1 Potassium Channel Mutant Muscle Proteins 030204 cardiovascular system & hematology Compound heterozygosity Sodium Channels MESH: KCNQ1 Potassium Channel Membrane Potentials NAV1.5 Voltage-Gated Sodium Channel 0302 clinical medicine Chlorocebus aethiops MESH: Animals Finland MESH: Heterozygote Genetics 0303 health sciences biology Genetic Carrier Screening MESH: Finland [SDV.BA]Life Sciences [q-bio]/Animal biology General Medicine 3. Good health MESH: COS Cells Long QT Syndrome Child Preschool COS Cells KCNQ1 Potassium Channel Mutation (genetic algorithm) Female Adult Heterozygote congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty MESH: Mutation Long QT syndrome hERG MESH: Ether-A-Go-Go Potassium Channels Transfection QT interval Sudden death MESH: Sodium Channels MESH: Muscle Proteins 03 medical and health sciences Internal medicine medicine Animals Humans MESH: Membrane Potentials [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology cardiovascular diseases 030304 developmental biology [SDV.GEN]Life Sciences [q-bio]/Genetics MESH: Humans MESH: Heterozygote Detection MESH: Long QT Syndrome business.industry MESH: Transfection MESH: Child Preschool MESH: Adult Heterozygote advantage medicine.disease MESH: Cercopithecus aethiops Ether-A-Go-Go Potassium Channels MESH: Male Endocrinology Mutation biology.protein business MESH: Female |
| Zdroj: | Annals of Medicine Annals of Medicine, Taylor & Francis, 2006, 38 (4), pp.294-304. ⟨10.1080/07853890600756065⟩ |
| ISSN: | 1365-2060 0785-3890 |
| DOI: | 10.1080/07853890600756065 |
| Popis: | BACKGROUND: Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death. AIM: The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study. METHODS: To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS-7 or HEK293 cells. RESULTS: The KCNQ1 IVS7-2A>G (KCNQ1-FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss-of-channel function. The HERG R176W (HERG-FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7-2A>G). When present simultaneously with an apparent LQTS-causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect. CONCLUSIONS: The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS. |
| Databáze: | OpenAIRE |
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