Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome)
| العنوان: | Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome) |
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| المؤلفون: | Valeria A. Sansone, Hubert Kwieciński, Matthew R. Donaldson, Rabi Tawil, Ying-Hui Fu, Saïd Bendahhou, Anna Fidziańska, Martin Tristani-Firouzi, Judy L. Jensen, Louis J. Ptáček, Giovanni Meola, Nikki M. Plaster, Angelika Hahn |
| المساهمون: | 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) |
| المصدر: | Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2002, xxx, pp.381-388 |
| بيانات النشر: | HAL CCSD, 2002. |
| سنة النشر: | 2002 |
| مصطلحات موضوعية: | Adult, Heart Defects, Congenital, Male, medicine.medical_specialty, Andersen Syndrome, Adolescent, Long QT syndrome, 030204 cardiovascular system & hematology, medicine.disease_cause, Article, Paralyses, Familial Periodic, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Andersen–Tawil syndrome, Internal medicine, medicine, Animals, Humans, cardiovascular diseases, Potassium Channels, Inwardly Rectifying, Child, 030304 developmental biology, 0303 health sciences, Mutation, business.industry, Kir2.1, Arrhythmias, Cardiac, Heart, Periodic paralysis, Cardiac action potential, Syndrome, General Medicine, Middle Aged, medicine.disease, 3. Good health, Electrophysiology, Long QT Syndrome, Endocrinology, cardiovascular system, Cardiology, Female, Rabbits, business |
| الوصف: | Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1. In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death. To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome. |
| اللغة: | English |
| تدمد: | 0021-9738 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02f833d9ebf0d4c4c93da7fbd053af2cTest https://hal.archives-ouvertes.fr/hal-00091062Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....02f833d9ebf0d4c4c93da7fbd053af2c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219738 |
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