RESUMEN
BACKGROUND: 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 (NaV1.5). BrS-related mutations have incomplete penetrance and variable expressivity within families. OBJECTIVE: The purpose of this study was to determine the role of patient-specific genetic background on the cellular and clinical phenotype among carriers of NaV1.5_p.V1525M. METHODS: 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. RESULTS: Our results showed a large reduction in INa 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 NaV1.5_p.V1525M channel. INa was not affected in hiPSC-CMs derived from a V1525M SNV carrier who also carries the NaV1.5_p.H558R polymorphism. Heterozygous expression of V1525M in HEK-293T cells produced a loss of INa function, not observed when this variant was expressed together with H558R. In addition, the antiarrhythmic drug mexiletine rescued INa function in hiPSC-CM. SCN5A expression was increased in the V1525M carrier who also expresses NaV1.5_p.H558R. CONCLUSION: Our results in patient-specific hiPSC-CM point to a dominant-negative effect of NaV1.5_p.V1525M, which can be reverted by the presence of NaV1.5_p.H558R. Overall, our data points to a role of patient-specific genetic background as a determinant for incomplete penetrance in BrS.
Asunto(s)
Síndrome de Brugada , Humanos , Sodio/metabolismo , Arritmias Cardíacas/metabolismo , Trastorno del Sistema de Conducción Cardíaco/metabolismo , Miocitos Cardíacos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/genética , Canal de Sodio Activado por Voltaje NAV1.5/metabolismoRESUMEN
Mitral valve prolapse (MVP) is a common valvular heart defect with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. Herein, we report a clinical and genetic investigation of a family with bileaflet MVP and a history of syncopes and resuscitated sudden cardiac death. Using family based whole exome sequencing, we identified two missense variants in the SCN5A gene. A rare variant SCN5A:p.Ala572Asp and the well-known functional SCN5A:p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father and sister carried only the SCN5A:p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as the potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and/or SCD history.
Asunto(s)
Prolapso de la Válvula Mitral , Humanos , Adulto Joven , Femenino , Prolapso de la Válvula Mitral/genética , Prolapso de la Válvula Mitral/complicaciones , Arritmias Cardíacas/genética , Arritmias Cardíacas/complicaciones , Muerte Súbita Cardíaca/etiología , Síncope/complicacionesRESUMEN
Host genetic factors have been proposed as determinants of the variable progression of Chagas disease (ChD). Two polymorphisms, H558R and A572D, of the voltage-gated sodium channel α-subunit SCN5A gene were studied in chagasic patients in order to determine their contribution to the susceptibility to the development and/or to the progression of the cardiovascular disease. A total of 104 patients were classified as seronegative or seropositive for Trypanosoma cruzi antibodies. Clinical evaluation, electrocardiograms (ECG) and echocardiograms (Echo) were performed to detect any conduction and/or structural alteration. Patients were classified into: G1: without ECG and/or Echo alterations, G2: with ECG alterations and G3: with ECG and Echo alterations. H558R and A572D polymorphisms were detected by PCR. Cardiac alterations were more frequent in G2 + G3 seropositive patients. For H558R polymorphism, the C allele was significantly increased in seropositive G2 + G3 patients (P = 0.049. OR = 2.08; 95% CI = 1.12-4.33). When comparing the disease cardiac progression (G2 vs G3), the genotypes from the H558R polymorphism were associated to more intense cardiac alterations (P = 0.018). For A572D polymorphism, no associations were found. The results suggest a possible involvement of SCN5A polymorphisms in the susceptibility to chronic ChD and the disease progression, contributing to the elucidation of the molecular mechanism underlying this complex myocardiopathy. In this regard, this is the first work that studies this gene in the context of chagasic cardiomyopathy.