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Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R.
Larasati, Yonika A; Solis, Gonzalo P; Koval, Alexey; Griffiths, Silja T; Berentsen, Ragnhild; Aukrust, Ingvild; Lesca, Gaetan; Chatron, Nicolas; Ville, Dorothée; Korff, Christian M; Katanaev, Vladimir L.
Afiliación
  • Larasati YA; Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
  • Solis GP; Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
  • Koval A; Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
  • Griffiths ST; Department of Pediatrics, Haukeland University Hospital, 5009 Bergen, Norway.
  • Berentsen R; Department of Medical Genetics, Haukeland University Hospital, 5009 Bergen, Norway.
  • Aukrust I; Department of Medical Genetics, Haukeland University Hospital, 5009 Bergen, Norway.
  • Lesca G; Department of Clinical Science, University of Bergen, 5008 Bergen, Norway.
  • Chatron N; Department of Medical Genetics, University Hospital of Lyon, 69002 Lyon, France.
  • Ville D; Department of Medical Genetics, University Hospital of Lyon, 69002 Lyon, France.
  • Korff CM; Pediatric Neurology Department, University Hospital of Lyon, 69002 Lyon, France.
  • Katanaev VL; Pediatric Neurology Unit, University Hospitals of Geneva, CH-1211 Geneva, Switzerland.
Cells ; 12(20)2023 10 17.
Article en En | MEDLINE | ID: mdl-37887313
De novo mutations in GNAO1, the gene encoding the major neuronal G protein Gαo, cause a spectrum of pediatric encephalopathies with seizures, motor dysfunction, and developmental delay. Of the >80 distinct missense pathogenic variants, many appear to uniformly destabilize the guanine nucleotide handling of the mutant protein, speeding up GTP uptake and deactivating GTP hydrolysis. Zinc supplementation emerges as a promising treatment option for this disease, as Zn2+ ions reactivate the GTP hydrolysis on the mutant Gαo and restore cellular interactions for some of the mutants studied earlier. The molecular etiology of GNAO1 encephalopathies needs further elucidation as a prerequisite for the development of efficient therapeutic approaches. In this work, we combine clinical and medical genetics analysis of a novel GNAO1 mutation with an in-depth molecular dissection of the resultant protein variant. We identify two unrelated patients from Norway and France with a previously unknown mutation in GNAO1, c.509C>G that results in the production of the Pro170Arg mutant Gαo, leading to severe developmental and epileptic encephalopathy. Molecular investigations of Pro170Arg identify this mutant as a unique representative of the pathogenic variants. Its 100-fold-accelerated GTP uptake is not accompanied by a loss in GTP hydrolysis; Zn2+ ions induce a previously unseen effect on the mutant, forcing it to lose the bound GTP. Our work combining clinical and molecular analyses discovers a novel, biochemically distinct pathogenic missense variant of GNAO1 laying the ground for personalized treatment development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encefalopatías Límite: Child / Humans Idioma: En Revista: Cells Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Suiza
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: Encefalopatías Límite: Child / Humans Idioma: En Revista: Cells Año: 2023 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Suiza