Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R

• Published in: Cells (Basel, Switzerland) Switzerland), 2023-10, Vol.12 (20), p.2469
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Brain Diseases; case report; Case reports; Child; Children; dominant mutation; Encephalopathy; Epilepsy; G proteins; GNAO1; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Proteins - metabolism; Guanosine Triphosphate; Gαo; Humans; Hydrolysis; Ions - metabolism; Localization; Mutants; Mutation; Mutation - genetics; pediatric encephalopathy; Pediatrics; Plasmids; Proteins; Seizures; Zinc
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12202469

De novo mutations in , 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 ions reactivate the GTP hydrolysis on the mutant Gαo and restore cellular interactions for some of the mutants studied earlier. The molecular etiology of 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 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 , 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 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 laying the ground for personalized treatment development.