Your browser doesn't support javascript.
loading
Pathogenicity of de novo CACNA1D Ca2+ channel variants predicted from sequence co-variation.
Tang, Xuechen; Ortner, Nadine J; Nikonishyna, Yuliia V; Fernández-Quintero, Monica L; Kokot, Janik; Striessnig, Jörg; Liedl, Klaus R.
Afiliación
  • Tang X; Department of General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020, Innsbruck, Austria.
  • Ortner NJ; Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020, Innsbruck, Austria.
  • Nikonishyna YV; Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020, Innsbruck, Austria.
  • Fernández-Quintero ML; Department of General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020, Innsbruck, Austria.
  • Kokot J; Department of General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020, Innsbruck, Austria.
  • Striessnig J; Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020, Innsbruck, Austria. Joerg.Striessnig@uibk.ac.at.
  • Liedl KR; Department of General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020, Innsbruck, Austria. Klaus.Liedl@uibk.ac.at.
Eur J Hum Genet ; 32(9): 1065-1073, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38553610
ABSTRACT
Voltage-gated L-type Cav1.3 Ca2+ channels support numerous physiological functions including neuronal excitability, sinoatrial node pacemaking, hearing, and hormone secretion. De novo missense mutations in the gene of their pore-forming α1-subunit (CACNA1D) induce severe gating defects which lead to autism spectrum disorder and a more severe neurological disorder with and without endocrine symptoms. The number of CACNA1D variants reported is constantly rising, but their pathogenic potential often remains unclear, which complicates clinical decision-making. Since functional tests are time-consuming and not always available, bioinformatic tools further improving pathogenicity potential prediction of novel variants are needed. Here we employed evolutionary analysis considering sequences of the Cav1.3 α1-subunit throughout the animal kingdom to predict the pathogenicity of human disease-associated CACNA1D missense variants. Co-variation analyses of evolutionary information revealed residue-residue couplings and allowed to generate a score, which correctly predicted previously identified pathogenic variants, supported pathogenicity in variants previously classified as likely pathogenic and even led to the re-classification or re-examination of 18 out of 80 variants previously assessed with clinical and electrophysiological data. Based on the prediction score, we electrophysiologically tested one variant (V584I) and found significant gating changes associated with pathogenic risks. Thus, our co-variation model represents a valuable addition to complement the assessment of the pathogenicity of CACNA1D variants completely independent of clinical diagnoses, electrophysiology, structural or biophysical considerations, and solely based on evolutionary analyses.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Canales de Calcio Tipo L Límite: Humans Idioma: En Revista: Eur J Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mutación Missense / Canales de Calcio Tipo L Límite: Humans Idioma: En Revista: Eur J Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido