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SCN5A compound heterozygosity mutation in Brugada syndrome: Functional consequences and the implication for pharmacological treatment.
Joviano-Santos, J V; Santos-Miranda, A; Neri, E A; Fonseca-Alaniz, M H; Krieger, J E; Pereira, A C; Roman-Campos, D.
Afiliación
  • Joviano-Santos JV; Laboratory of CardioBiology, Department of Biophysics, Federal University of São Paulo, Brazil.
  • Santos-Miranda A; Laboratory of CardioBiology, Department of Biophysics, Federal University of São Paulo, Brazil.
  • Neri EA; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.
  • Fonseca-Alaniz MH; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.
  • Krieger JE; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.
  • Pereira AC; Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.
  • Roman-Campos D; Laboratory of CardioBiology, Department of Biophysics, Federal University of São Paulo, Brazil. Electronic address: drcampos@unifesp.br.
Life Sci ; 278: 119646, 2021 Aug 01.
Article en En | MEDLINE | ID: mdl-34048814
AIMS: SCN5A gene encodes the α-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. KEY 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Brugada / Canal de Sodio Activado por Voltaje NAV1.5 / Mutación con Pérdida de Función Límite: Humans Idioma: En Revista: Life Sci Año: 2021 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Brugada / Canal de Sodio Activado por Voltaje NAV1.5 / Mutación con Pérdida de Función Límite: Humans Idioma: En Revista: Life Sci Año: 2021 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Países Bajos