SCN5A compound heterozygosity mutation in Brugada syndrome: Functional consequences and the implication for pharmacological treatment

Author(s)

Joviano-Santos, V, J. ; Santos-Miranda, A. ^[1] ; Neri, E. A. ^[2] ; Fonseca-Alaniz, M. H. ^[2] ; Krieger, J. E. ^[2] ; Pereira, A. C. ^[2] ; Roman-Campos, D. ^[1]

Affiliation

^[1] Joviano-Santos, J., V, Univ Fed Sao Paulo, Dept Biophys, Lab CardioBiol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Med Sch, Sao Paulo - Brazil

• Document type: Journal article
• Source: Life Sciences; v. 278, AUG 1 2021.
• Web of Science Citations: 0

Abstract

Aims: SCN5A gene encodes the alpha-subunit of Nav1.5, mainly found in the human heart. SCN5A variants are the most common genetic alterations associated with Brugada syndrome (BrS). In rare cases, compound heterozygosity is observed; however, its functional consequences are poorly understood. We aimed to analyze the functional impact of de novo Nav1.5 mutations in compound heterozygosity in distinct alleles (G400R and T1461S positions) previously found in a patient with BrS. Moreover, we evaluated the potential benefits of quinidine to improve the phenotype of mutant Na+ channels in vitro. Materials and methods: The functional properties of human wild-type and Nav1.5 variants were evaluated using whole-cell patch-clamp and immunofluorescence techniques in transiently expressed human embryonic kidney (HEK293) cells. K ey findings: Both variants occur in the highly conservative positions of SCN5A. Although all variants were expressed in the cell membrane, a significant reduction in the Na+ current density (except for G400R alone, which was undetected) was observed along with abnormal biophysical properties, once the variants were expressed in homozygosis and heterozygosis. Interestingly, the incubation of transfected cells with quinidine partially rescued the biophysical properties of the mutant Na+ channel. Significance: De novo compound heterozygosis mutations in SNC5A disrupt the Na+ macroscopic current. Quinidine could partially reverse the in vitro loss-of-function phenotype of Na+ current. Thus, our data provide, for the first time, a detailed biophysical characterization of dysfunctional Na+ channels linked to compound heterozygosity in BrS as well as the benefits of the pharmacological treatment using quinidine on the biophysical properties of Nav1.5. (AU)

• FAPESP's process: 19/21304-4 - Arrhythmogenic mechanisms in right heart diseases
• Grantee: Danilo Roman Campos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/09861-1 - The role of late sodium current in the inherited and acquired cardiac arrhythmias: from the biophysics properties to new therapeutic targets
• Grantee: Danilo Roman Campos
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 18/20777-3 - Genetic variants of the Nav 1.5 sodium channel and its therapeutic implications.
• Grantee: Julliane Vasconcelos Joviano dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral