Journal
HEART RHYTHM
Volume 11, Issue 7, Pages 1202-1209Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2014.03.044
Keywords
SCN5A; SCN1B; Cardiac sodium channel; beta subunits; Sudden cardiac death; long QT syndrome
Categories
Funding
- CNIC-Translational [CNIC-03-2008]
- Spanish Ministry of Health [RD06/03/0018]
- ObraSocial La Caixa
- RETICS (Red Cardiovascular Enfermedades
- PFIS predoctoral fellowship [FI09/00336]
- Instituto de Salud Carlos III [CD09/00055]
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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 beta subunits have been associated with cardiac channelopathies, including SCN4B mutations in LQTS. OBJECTIVE To evaluate the role of mutations in the sodium channel beta subunits in LQTS. METHODS We screened for mutations in the genes encoding the 5 sodium beta 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-1cells, respectively, in the presence of beta 1b subunits. RESULTS The genetic screening revealed a novel mutation in the SCN1Bb gene (beta 1bP213T) in an 8-year-old boy. Our electrophysiological analysis revealed that beta 1bP213T increases late sodium current. In addition, beta 1bP213T subtly altered Na(v)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 beta 1b was overexpressed compared with beta 1bWT. 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.
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