dc.contributor.author | Larasati, Yonika A. | |
dc.contributor.author | Solis, Gonzalo P. | |
dc.contributor.author | Koval, Alexey | |
dc.contributor.author | Griffiths, Silja Torvik | |
dc.contributor.author | Berentsen, Ragnhild Drage | |
dc.contributor.author | Aukrust, Ingvild | |
dc.contributor.author | Lesca, Gaetan | |
dc.contributor.author | Chatron, Nicolas | |
dc.contributor.author | Ville, Dorothée | |
dc.contributor.author | Korff, Christian M. | |
dc.contributor.author | Katanaev, Vladimir L. | |
dc.date.accessioned | 2024-08-01T08:51:23Z | |
dc.date.available | 2024-08-01T08:51:23Z | |
dc.date.created | 2023-11-14T13:16:27Z | |
dc.date.issued | 2023 | |
dc.identifier.issn | 2073-4409 | |
dc.identifier.uri | https://hdl.handle.net/11250/3144008 | |
dc.description.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 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. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | MDPI | en_US |
dc.rights | Navngivelse 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/deed.no | * |
dc.title | Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R | en_US |
dc.type | Journal article | en_US |
dc.type | Peer reviewed | en_US |
dc.description.version | publishedVersion | en_US |
dc.rights.holder | Copyright 2023 The Author(s) | en_US |
dc.source.articlenumber | 2469 | en_US |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.doi | 10.3390/cells12202469 | |
dc.identifier.cristin | 2196479 | |
dc.source.journal | Cells | en_US |
dc.identifier.citation | Cells. 2023, 12 (20), 2469. | en_US |
dc.source.volume | 12 | en_US |
dc.source.issue | 20 | en_US |