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A missense mutation in the sodium channel β1b subunit reveals SCN1B as a susceptibility gene underlying long QT syndrome.
- Source :
- Heart Rhythm; Jul2014, Vol. 11 Issue 7, p1202-1209, 8p
- Publication Year :
- 2014
-
Abstract
- Background: Long QT syndrome (LQTS) is associated with sudden cardiac death and the prolongation of the QT interval on the electrocardiogram. A comprehensive screening of all genes previously associated with this disease leaves 30% of the patients without a genetic diagnosis. Pathogenic mutations in the sodium channel β subunits have been associated with cardiac channelopathies, including SCN4B mutations in LQTS. Objective: To evaluate the role of mutations in the sodium channel β subunits in LQTS. Methods: We screened for mutations in the genes encoding the 5 sodium β subunits (SCN1B isoforms a and b, SCN2B, SCN3B, and SCN4B) from 30 nonrelated patients who were clinically diagnosed with LQTS without mutations in common LQTS-related genes. We used the patch-clamp technique to study the properties of sodium currents and the action potential duration in human embryonic kidney and HL-1 cells, respectively, in the presence of β1b subunits. Results: The genetic screening revealed a novel mutation in the SCN1Bb gene (β1bP213T) in an 8-year-old boy. Our electrophysiological analysis revealed that β1bP213T increases late sodium current. In addition, β1bP213T subtly altered Na<subscript>v</subscript>1.5 function by shifting the window current, accelerating recovery from inactivation, and decreasing the slow inactivation rate. Moreover, experiments using HL-1 cells revealed that the action potential duration significantly increases when the mutant β1b was overexpressed compared with β1bWT. Conclusion: These data revealed SCN1Bb as a susceptibility gene responsible for LQTS, highlighting the importance of continuing the search for new genes and mechanisms to decrease the percentage of patients with LQTS remaining without genetic diagnosis. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 15475271
- Volume :
- 11
- Issue :
- 7
- Database :
- Supplemental Index
- Journal :
- Heart Rhythm
- Publication Type :
- Academic Journal
- Accession number :
- 96661032
- Full Text :
- https://doi.org/10.1016/j.hrthm.2014.03.044