Cortical neurons obtained from patient-derived iPSCs with GNAO1 p.G203R variant show altered differentiation and functional properties

Heliyon, Journal Year: 2024, Volume and Issue: 10(5), P. e26656 - e26656

Published: Feb. 21, 2024

Pathogenic variants in the

Language: Английский

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Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(15)

Published: June 14, 2024

GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G-protein Gαo. Of >80 pathogenic mutations, most are single amino acid substitutions spreading across Gαo sequence. We perform extensive characterization of mutants showing abnormal GTP uptake and hydrolysis, deficiencies to bind Gβγ RGS19. Plasma membrane localization is decreased for a subset mutations that leads epilepsy; dominant interactions with GPCRs also emerge more severe mutants. Pathogenic massively gain interaction Ric8A and, surprisingly, Ric8B proteins, delocalizing them from cytoplasm Golgi. these two mandatory Gα-subunit chaperones, normally responsible Gαi/o, Gαq, Gα12/13 subfamilies, solely Gαs/olf. Ric8A/B mediate disease dominance when engaging neomorphic through disbalancing G protein signaling networks. As strength Gαo-Ric8B correlates severity, our study further identifies an efficient biomarker predictor clinical manifestations encephalopathies. Our work discovers molecular mechanism underlying offers insights other maladies caused by misfunctioning genetic diseases.

Language: Английский

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Clinical and Molecular Profiling in GNAO1 Permits Phenotype–Genotype Correlation

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(9), P. 1578 - 1591

Published: June 16, 2024

Abstract Background Defects in GNAO1 , the gene encoding major neuronal G‐protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain different phenotypes. Objectives We aimed analyze clinical phenotype characterization ‐related Methods Patients were recruited collaboration with Spanish Association. For patient phenotyping, direct evaluation, analysis homemade‐videos, an online questionnaire completed by families analyzed. studied Gαo cellular expression, interactions partner proteins, binding guanosine triphosphate (GTP) G‐protein‐coupled receptors (GPCRs). Results Eighteen patients genetic defects had complex disorder, central hypotonia, Eleven showed neurological deterioration, recurrent hyperkinetic crisis partial recovery, secondary complications leading death three cases. Deep brain stimulation improved crisis, but inconsistent benefits dystonia. The caused pathogenic aberrant GTP hydrolysis activities, inability interact partners, reduced coupling GPCRs. Decreased localization plasma membrane was correlated “developmental epileptic encephalopathy 17.” observed genotype–phenotype correlation, variants position 203 developmental encephalopathy, whereas those 209 disorder involuntary movements. Milder phenotypes associated other such as del.16q12.2q21 I344del. Conclusion highlight complexity motor phenotype, which characterized fluctuations throughout day, distinct post‐hyperkinetic state. confirm molecular‐based correlation for specific variants. © 2024 Author(s). Movement Disorders published Wiley Periodicals LLC on behalf International Parkinson Disorder Society.

Language: Английский

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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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Spectrum of Inherited Childhood‐Onset Dystonia: Case Series of 19 Families With Genotype and Phenotype Characterization Highlighting the Treatable Causes

Clinical Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

ABSTRACT Childhood‐onset dystonia, a clinically and genetically diverse group of disorders, can be challenging to diagnose. Information on the genotype phenotype spectrum in Indian population is limited. This study reports clinical molecular findings monogenic childhood‐onset dystonia 22 individuals from 19 families. Complex was most frequent type, followed by combined isolated forms. A total 23 variants across 17 genes were identified, including nine novel ones. These disorders include four autosomal dominant, one X‐linked recessive, mitochondrial, remaining 11 recessive conditions. Five potentially treatable treatment initiated three families, showing satisfactory responses, particularly dopa‐responsive dystonias. Our contributes additional genes— CYP27A1 , NDUFAF3 FUCA1 FIG4 —to list associated with complex dystonia. Exome sequencing proved crucial diagnosing etiology identifying forms, aiding genetic counseling. emphasizes significance using NGS for early diagnosis enable timely targeted therapies, offer precise counseling prevent recurrence family.

Language: Английский

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Developmental and epileptic encephalopathy 56 due to YWHAG variants: 12 new cases and review of the literature.

European Journal of Paediatric Neurology, Journal Year: 2024, Volume and Issue: 53, P. 63 - 72

Published: Oct. 9, 2024

Language: Английский

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Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies

Biomolecules, Journal Year: 2025, Volume and Issue: 15(1), P. 133 - 133

Published: Jan. 15, 2025

Developmental and epileptic encephalopathies (DEEs) are a group of neuropediatric diseases associated with seizures, severe delay or regression psychomotor development, cognitive behavioral deficits. What sets DEEs apart is their complex interplay epilepsy developmental delay, often driven by genetic factors. These two aspects influence one another but can develop independently, creating diagnostic therapeutic challenges. Intellectual disability complicates potential treatment. Pathogenic variants found in 30–50% patients DEE. Many genes mutated encode ion channels, causing current conduction disruptions known as channelopathies. Although channelopathies indeed make up significant proportion DEE cases, many other mechanisms have been identified: impaired neurogenesis, metabolic disorders, disruption dendrite axon growth, maintenance synapse formation abnormalities —synaptopathies. Here, we review recent publications on non-channelopathies an emphasis the linking epileptiform activity intellectual disability. We focus three major describe several recently identified involved pathogenesis

Language: Английский

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Exploring the Impact of Dyskinetic Crises in GNAO1‐Related Disorders: A Survey for Parents and Caregivers

Movement Disorders Clinical Practice, Journal Year: 2025, Volume and Issue: unknown

Published: April 25, 2025

Abstract Background GNAO1 ‐related disorders ( ‐RD) encompass developmental delay, epilepsy and movement disorders, including dyskinetic crises. Objectives To explore the characteristics of crises in ‐RD, their impact challenges parents face. Methods A cross‐sectional EU survey 26 children with ‐RD collected demographic, clinical, management‐related data. Results Dyskinetic were experienced by 80% children. They began at a mean age 4.17 ± 2.61 years varied widely frequency duration, triggers infections emotions. significantly impacted quality life (QoL), motor function, emotional well‐being. Medications variably effective, 10 underwent deep brain stimulation mixed outcomes. Parents reported managing accessing support services, financial burdens. Conclusions QoL present complex management challenges. Variability outcomes underscores need for optimized treatment protocols, better coordination, accessible resources affected families.

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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Diverse faces of GNAO1: mild forms in epilepsy and autism

Journal of Neurology, Journal Year: 2024, Volume and Issue: 271(7), P. 3777 - 3781

Published: May 10, 2024

Language: Английский

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