Biophysical and Molecular Characterization of a Novel De Novo KCNJ2 Mutation Associated With Andersen-Tawil Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia Mimicry
| Autor: | Hector Barajas-Martinez, Dan Hu, Gabriel Caceres, Charles Antzelevitch, Elena Burashnikov, Mayurika Desai, Gustavo Ontiveros, Jorge Scaglione |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Tachycardia
medicine.medical_specialty Mutation Andersen Syndrome Mutant Periodic paralysis Biology medicine.disease medicine.disease_cause Catecholaminergic polymorphic ventricular tachycardia Andersen–Tawil syndrome Endocrinology Internal medicine Genetics medicine medicine.symptom Cardiology and Cardiovascular Medicine Flecainide Genetics (clinical) medicine.drug |
| Zdroj: | Circulation: Cardiovascular Genetics. 4:51-57 |
| ISSN: | 1942-3268 1942-325X |
| DOI: | 10.1161/circgenetics.110.957696 |
| Popis: | Background— Mutations in KCNJ2 , the gene encoding the human inward rectifier potassium channel Kir2.1 (I K1 or I Kir2.1 ), have been identified in Andersen-Tawil syndrome. Andersen-Tawil syndrome is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia. Methods and Results— Our proband displayed dysmorphic features including micrognathia, clinodactyly, and syndactyly and exhibited multiform extrasystoles and bidirectional ventricular tachycardia both at rest and during exercise testing. The patient's symptoms continued after administration of nadolol but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p.R260P) in KCNJ2 . Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild-type human KCNJ2 cDNA (WT- KCNJ2 ) yielded robust I Kir2.1 but no measurable current in cells expressing the R260P mutant. Coexpression of WT and R260P- KCNJ2 (heterozygous expression) yielded a markedly reduced inward I Kir2.1 compared with WT alone (−36.5±9.8 pA/pF versus −143.5±11.4 pA/pF, n=8 for both, P Kir2.1 measured at −50 mV was also markedly reduced with the heterozygous expression versus WT (0.52±5.5 pA/pF versus 23.4±6.7 pA/pF, n=8 for both, P KCNJ2 channels. Conclusions— We report a novel de novo KCNJ2 mutation associated with classic phenotypic features of Andersen-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry. The R260P mutation produces a strong dominant negative effect leading to marked suppression of I K1 secondary to a trafficking defect. |
| Databáze: | OpenAIRE |
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