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Loss of sodium current caused by a Brugada syndrome–associated variant is determined by patient-specific genetic background.
- Source :
- Heart Rhythm; Mar2024, Vol. 21 Issue 3, p331-339, 9p
- Publication Year :
- 2024
-
Abstract
- Brugada syndrome (BrS) is an inherited cardiac arrhythmogenic disease that predisposes patients to sudden cardiac death. It is associated with mutations in SCN5A , which encodes the cardiac sodium channel alpha subunit (Na V 1.5). BrS-related mutations have incomplete penetrance and variable expressivity within families. The purpose of this study was to determine the role of patient-specific genetic background on the cellular and clinical phenotype among carriers of Na V 1.5_p.V1525M. We studied sodium currents from patient-specific human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and heterologously transfected human embryonic kidney (HEK) tsA201 cells using the whole-cell patch-clamp technique. We determined gene and protein expression by quantitative polymerase chain reaction, RNA sequencing, and western blot and performed a genetic panel for arrhythmogenic diseases. Our results showed a large reduction in I Na density in hiPSC-CM derived from 2 V1525M single nucleotide variant (SNV) carriers compared with hiPSC-CM derived from a noncarrier, suggesting a dominant-negative effect of the Na V 1.5_p.V1525M channel. I Na was not affected in hiPSC-CMs derived from a V1525M SNV carrier who also carries the Na V 1.5_p.H558R polymorphism. Heterozygous expression of V1525M in HEK-293T cells produced a loss of I Na function, not observed when this variant was expressed together with H558R. In addition, the antiarrhythmic drug mexiletine rescued I Na function in hiPSC-CM. SCN5A expression was increased in the V1525M carrier who also expresses Na V 1.5_p.H558R. Our results in patient-specific hiPSC-CM point to a dominant-negative effect of Na V 1.5_p.V1525M, which can be reverted by the presence of Na V 1.5_p.H558R. Overall, our data points to a role of patient-specific genetic background as a determinant for incomplete penetrance in BrS. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15475271
- Volume :
- 21
- Issue :
- 3
- Database :
- Supplemental Index
- Journal :
- Heart Rhythm
- Publication Type :
- Academic Journal
- Accession number :
- 175343274
- Full Text :
- https://doi.org/10.1016/j.hrthm.2023.11.019