Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case

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

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A Personalized 14-3-3 Disease-Targeting Workflow Yields Repositioning Drug Candidates

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

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A personalized 14-3-3 disease-targeting workflow yields repositioning drug candidates

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

Published: Jan. 23, 2025

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

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Novel Mutation at Cys225 in GNAO1‐Associated Developmental and Epileptic Encephalopathies: Clinical, Molecular, and Pharmacological Profiling of Case Studies

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

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Reply to: “Clinical and Molecular Profiling in GNAO1 Permits Phenotype–Genotype Correlation”

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(11), P. 2124 - 2125

Published: Nov. 1, 2024

Language: Английский

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Genetic Diversity and Expanded Phenotypes in Dystonia: Insights from Large-Scale Exome Sequencing

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

Abstract Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (∼25%) identification several disease-linked genes, etiology in patients remains elusive. Moreover, understanding correlations between manifestation genetic variants has become increasingly complex. To comprehensively unravel dystonia’s spectrum, we performed exome sequencing on 1,924 dystonia [40.3% male, 92.9% White, 93.2% isolated dystonia, median age at onset (AAO) 33 years], including 1,895 index patients, who were previously genetically unsolved. The sample was mainly based two registries (DysTract Coalition). Further, 72 additional Asian ethnicity, from Malaysia, also included. We prioritized with negative prescreening, early AAO, positive family history, multisite involvement dystonia. Rare genes linked to ( n =405) examined. Variants confirmed via Sanger sequencing, segregation analysis when possible. identified 137 distinct likely pathogenic or (according ACMG criteria) across 51 163/1,924 [42.9% 85.9% 68.7% AAO 19 years]. This included 153/1,895 resulting a diagnostic yield 8.1%. Notably, 77/137 (56.2%) these novel, recurrent EIF2AK2 , VPS16 KCNMA1 SLC2A1 novel variant types such as splice site KMT2B supported functional evidence. Additionally, 321 (16.9%) harbored uncertain significance 102 genes. frequently implicated THAP1 GCH1 SGCE GNAL KMT2B. Presumably less well-established found, KIF1A ZMYND11. At least six (in ADCY5 GNB1 IR2BPL, KCNN2 ) occurred de novo, supporting pathogenicity. ROC curve indicated that presence generalized strongest predictors diagnosis, yields 28.6% 20.4% those < 30 years. study provides comprehensive examination landscape revealing valuable insights into frequency dystonia-linked their associated phenotypes. It underscores utility establishing diagnoses within this heterogeneous condition. presumably almost 10% patients. Our findings reaffirm candidate expand phenotypic spectrum some include prominent, sometimes

Language: Английский

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Response to Mortimer et al. “Clinical and molecular profiling in GNAO1 permits phenotype–genotype correlation”

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(11), P. 2125 - 2126

Published: Nov. 1, 2024

Language: Английский

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