Scientific article
Open access

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

Published inCells, vol. 12, no. 20, 2469
Publication date2023-10-17
First online date2023-10-17

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.

  • G proteins
  • GNAO1
  • GTP binding
  • Gαo
  • Case report
  • Dominant mutation
  • Drug discovery
  • Intracellular localization
  • Molecular etiology
  • Pediatric encephalopathy
  • Personalized medicine
  • Protein–protein interactions
Citation (ISO format)
LARASATI, Yonika Arum et al. Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R. In: Cells, 2023, vol. 12, n° 20, p. 2469. doi: 10.3390/cells12202469
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ISSN of the journal2073-4409

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Creation10/30/2023 12:11:51 PM
First validation10/30/2023 2:39:41 PM
Update time10/30/2023 2:39:41 PM
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