Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R
Yonika A Larasati1, Gonzalo P Solis1, Alexey Koval1
1Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.
Insights
De novo mutations in the GNAO1 gene cause pediatric encephalopathies. A novel Pro170Arg GNAO1 variant shows unique molecular behavior, offering new avenues for personalized GNAO1 encephalopathy treatments.
Area of Science:
- Neurogenetics
- Molecular Biology
- Biochemistry
Background:
- De novo mutations in GNAO1 cause pediatric encephalopathies, characterized by seizures, motor dysfunction, and developmental delay.
- Most pathogenic GNAO1 variants destabilize guanine nucleotide handling, affecting GTP uptake and hydrolysis.
- Zinc supplementation has shown promise in reactivating GTP hydrolysis for some GNAO1 mutants.
Purpose of the Study:
- To investigate the molecular etiology of GNAO1 encephalopathies by analyzing a novel mutation.
- To combine clinical and medical genetics analysis with in-depth molecular dissection of the resultant protein variant.
- To identify and characterize a novel, biochemically distinct pathogenic GNAO1 missense variant.
Main Methods:
- Clinical and medical genetics analysis of two unrelated patients with a novel GNAO1 mutation (c.509C>G).
- Molecular investigation of the Pro170Arg GNAO1 mutant protein.
- Biochemical assays to assess GTP uptake, GTP hydrolysis, and the effect of Zn2+ ions on the mutant protein.
Main Results:
- Identified two patients with a novel GNAO1 mutation (c.509C>G) causing severe developmental and epileptic encephalopathy.
- The Pro170Arg GNAO1 mutant exhibits a 100-fold accelerated GTP uptake without impaired GTP hydrolysis.
- Zn2+ ions induced a unique effect, causing the Pro170Arg mutant to release bound GTP.
Conclusions:
- Discovered a novel, biochemically distinct pathogenic missense variant of GNAO1 (Pro170Arg).
- The Pro170Arg mutant presents unique molecular characteristics compared to previously identified GNAO1 variants.
- This finding provides a foundation for developing personalized treatment strategies for GNAO1-related encephalopathies.
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.
