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- Title
Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome.
- Authors
Zaklyazminskaya, Elena; Polyak, Margarita; Shestak, Anna; Sadekova, Mariam; Komoliatova, Vera; Kiseleva, Irina; Makarov, Leonid; Podolyak, Dmitriy; Glukhov, Grigory; Zhang, Han; Abramochkin, Denis; Sokolova, Olga S.
- Abstract
Background: The KCNJ2 gene encodes inward rectifier Kir2.1 channels, maintaining resting potential and cell excitability. Presumably, clinical phenotypes of mutation carriers correlate with ion permeability defects. Loss-of-function mutations lead to QTc prolongation with variable dysmorphic features, whereas gain-of-function mutations cause short QT syndrome and/or atrial fibrillation. Methods: We screened 210 probands with Long QT syndrome for mutations in the KCNJ2 gene. The electrophysiological study was performed for the p.Val93Ile variant in the transfected CHO-K1 cells. Results: We found three rare genetic variants, p.Arg67Trp, p.Val93Ile, and p.R218Q, in three unrelated LQTS probands. Probands with p.Arg67Trp and p.R218Q had a phenotype typical for Andersen-Tawil (ATS), and the p.Val93Ile carrier had lone QTc prolongation. Variant p.Val93Ile was initially described as a gain-of-function pathogenic mutation causing familial atrial fibrillation. We validated electrophysiological features of this variant in CHO-K1 cells, but no family members of these patients had atrial fibrillation. Using ACMG (2015) criteria, we re-assessed this variant as a variant of unknown significance (class III). Conclusions: LQT7 is a rare form of LQTS in Russia, and accounts for 1% of the LQTS cohort. Variant p.Val93Ile leads to a gain-of-function effect in the different cell lines, but its clinical appearance is not so consistent. The clinical significance of this variant might be overestimated.
- Subjects
RUSSIA; LONG QT syndrome; GAIN-of-function mutations; MEMBRANE potential; GENETIC variation; PATIENT-family relations
- Publication
Genes, 2022, Vol 13, Issue 4, p559
- ISSN
2073-4425
- Publication type
Article
- DOI
10.3390/genes13040559