Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R DOI Creative Commons
Yonika Arum Larasati, Gonzalo P. Solis, Alexey Koval

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(20), P. 2469 - 2469

Published: Oct. 17, 2023

De novo mutations in GNAO1, the gene encoding major neuronal G protein Gαo, cause a spectrum of pediatric encephalopathies with seizures, motor dysfunction, and developmental delay. Of >80 distinct missense pathogenic variants, many appear to uniformly destabilize guanine nucleotide handling mutant protein, speeding up GTP uptake deactivating hydrolysis. Zinc supplementation emerges as promising treatment option for this disease, Zn2+ ions reactivate hydrolysis on Gαo restore cellular interactions some mutants studied earlier. The molecular etiology GNAO1 needs further elucidation prerequisite development efficient therapeutic approaches. In work, we combine clinical medical genetics analysis novel mutation an in-depth dissection resultant variant. We identify two unrelated patients from Norway France previously unknown c.509C>G that results production Pro170Arg leading severe epileptic encephalopathy. Molecular investigations unique representative variants. Its 100-fold-accelerated is not accompanied by loss hydrolysis; induce unseen effect mutant, forcing it lose bound GTP. Our work combining analyses discovers novel, biochemically variant laying ground personalized development.

Language: Английский

Clinical-molecular profiling of atypical GNAO1 patients: Novel pathogenic variants, unusual manifestations, and severe molecular dysfunction DOI Creative Commons
Gonzalo P. Solis, Federica Rachele Danti, Yonika Arum Larasati

et al.

Genes & Diseases, Journal Year: 2025, Volume and Issue: unknown, P. 101522 - 101522

Published: Jan. 1, 2025

Language: Английский

Citations

1
Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case DOI Creative Commons
Yonika Arum Larasati, Moritz Thiel, Alexey Koval

et al.

Med, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Context and significanceMutations in the gene GNAO1 lead to severe sometimes fatal pediatric encephalopathies that are poorly responsive current treatments. The pathogenic mutations produce aberrant variants of a major neuronal signaling protein Gαo. Salts zinc partially correct abnormal functioning mutant Here, dozens Gαo shown fall into distinct groups their responsiveness zinc, providing ground for patient stratification. Zinc supplementation is safe mouse disease models, leading first-in-human application. A 3-year-old with encephalopathy on oral administration shows strong improvement motor skills, cessation daily hyperkinetic crises, reduction epileptic seizures, without side effects. These findings set new standard care GNAO1-related disorders.Highlights•Mutations encoding encephalopathy•Pathogenic stratify 3 classes Zn2+•Zinc models•Successful study encephalopathySummaryBackgroundDe novo GNAO1—the G Gαo—cause other neurological deficiencies largely refractory available therapies. Zn2+ emerged restore guanosine triphosphate hydrolysis cellular interactions Gαo; dietary salt improves lifespan motoric function Drosophila model.MethodsUsing biochemical, animal, studies, we provide support stratification application acetate GNAO1-associated disorders.FindingsWe show 16 different missense cluster three Zn2+, safety model. We further describe treatment common variant c607G>A, p.Gly203Arg 50 mg (in form acetate) daily, as applied Wilson's disease. During 11 months treatment, dyskinetic improved Burke-Fahn Marsden Dystonia Rating Scale movement score, an excellent profile.ConclusionsOur warrant large-scale clinical trial might disorders.FundingThis work was funded by Russian Science Foundation (grant #21-15-00138) España.Graphical abstract

Language: Английский

Citations

6
A Personalized 14-3-3 Disease-Targeting Workflow Yields Repositioning Drug Candidates DOI Creative Commons
Yonika Arum Larasati, Gonzalo P. Solis, Alexey Koval

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(8), P. 559 - 559

Published: April 8, 2025

Rare diseases typically evade the application of standard drug discovery and development pipelines due to their understudied molecular etiology small market size. Herein, we report a rare disease-directed workflow that rapidly studies features disorder, establishes high-throughput screening (HTS) platform, conducts an HTS thousands approved drugs identify validate repositioning candidates. This study examines pediatric neurological disorder caused by de novo mutations in YWHAG, gene encoding scaffolding protein 14-3-3γ, discovers nuclear relocalization severe drop 14-3-3γ binding its phosphorylated partners as key pathogenic hotspot YWHAG mutations. We further established robust vitro platform screened ca. 3000 candidates restore deficient 14-3-3γ-phosphotarget interactions. Our can be applied other 14-3-3-related disorders upscaled for many diseases.

Language: Английский

Citations

0
A personalized 14-3-3 disease-targeting workflow yields repositioning drug candidates DOI Creative Commons
Yonika Arum Larasati, Gonzalo P. Solis, Alexey Koval

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Abstract Rare diseases typically evade the application of standard drug discovery and development pipeline due to their understudied molecular etiology small market size. Here, we report a rare disease-directed workflow that rapidly studies features disorder, establishes high-throughput screening (HTS) platform, conducts an HTS thousands approved drugs identify validate repositioning candidates. Applied pediatric neurological disorder caused by de novo mutations in YWHAG, gene encoding scaffolding protein 14-3-3γ, this discovers nuclear relocalization severe drop 14-3-3γ binding its phosphorylated partners as key pathogenic hotspot YWHAG mutations. We further established robust in vitro platform screened ca. 3000 candidates restore deficient 14-3-3γ-phosphotarget interactions. Our can be applied other 14-3-3-related disorders upscaled for many diseases.

Language: Английский

Citations

0
Development of an AAV-RNAi strategy to silence the dominant variant GNAO1 c.607G>A linked to encephalopathy DOI
Evgenii A. Lunev, Natalia V. Klementieva, Svetlana G. Vassilieva

et al.

Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Language: Английский

Citations

0
Novel Mutation at Cys225 in GNAO1‐Associated Developmental and Epileptic Encephalopathies: Clinical, Molecular, and Pharmacological Profiling of Case Studies DOI Creative Commons
Yonika Arum Larasati, Gonzalo P. Solis, Alexey Koval

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(5)

Published: May 1, 2025

ABSTRACT GNAO1 ‐associated disorders have a large spectrum of neurological symptoms, from early‐onset developmental and epileptic encephalopathies (DEE) to late‐onset movement disorders. First reported in 2013 now identified around 400 cases worldwide, this disease is caused by dominant, mostly de novo missense mutations , the gene encoding major neuronal G protein Gαo. Being immediate transducer number protein‐coupled receptors, Gαo plays crucial functions brain development physiology. Here, we discover novel mutation site Cys225 mutated Tyr or Arg pediatric individuals France China (p.(Cys225Tyr) p.(Cys225Arg), respectively), leading severe DEE. Molecular investigations characterize pathogenic variants as deficient interactions with guanine nucleotides physiological cellular partners Gαo, reduced stability plasma membrane localization strong neomorphic interaction chaperone Ric8A. Salts zinc, emerging promising targeted therapy for disorders, impose previously unseen effect on mutant accelerating loss its ability interact nucleotides. Our study, combining clinical, cellular, molecular, modeling approaches, describes deep insights into molecular etiology treatment perspectives form

Language: Английский

Citations

0
Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R DOI Creative Commons
Yonika Arum Larasati, Gonzalo P. Solis, Alexey Koval

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(20), P. 2469 - 2469

Published: Oct. 17, 2023

De novo mutations in GNAO1, the gene encoding major neuronal G protein Gαo, cause a spectrum of pediatric encephalopathies with seizures, motor dysfunction, and developmental delay. Of >80 distinct missense pathogenic variants, many appear to uniformly destabilize guanine nucleotide handling mutant protein, speeding up GTP uptake deactivating hydrolysis. Zinc supplementation emerges as promising treatment option for this disease, Zn2+ ions reactivate hydrolysis on Gαo restore cellular interactions some mutants studied earlier. The molecular etiology GNAO1 needs further elucidation prerequisite development efficient therapeutic approaches. In work, we combine clinical medical genetics analysis novel mutation an in-depth dissection resultant variant. We identify two unrelated patients from Norway France previously unknown c.509C>G that results production Pro170Arg leading severe epileptic encephalopathy. Molecular investigations unique representative variants. Its 100-fold-accelerated is not accompanied by loss hydrolysis; induce unseen effect mutant, forcing it lose bound GTP. Our work combining analyses discovers novel, biochemically variant laying ground personalized development.

Language: Английский

Citations

4