학술논문
Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R.
Document Type
Academic Journal
Author
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.; Department of Clinical Science, University of Bergen, 5008 Bergen, Norway.; Lesca G; Department of Medical Genetics, University Hospital of Lyon, 69002 Lyon, France.; Chatron N; Department of Medical Genetics, University Hospital of Lyon, 69002 Lyon, France.; Ville D; Pediatric Neurology Department, University Hospital of Lyon, 69002 Lyon, France.; Korff CM; Pediatric Neurology Unit, University Hospitals of Geneva, CH-1211 Geneva, Switzerland.; Katanaev VL; Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.; Institute of Life Sciences and Biomedicine, Far Eastern Federal University, Vladivostok 690090, Russia.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE
Subject
Language
English
Abstract
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 Zn 2+ 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; Zn 2+ 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.