GNAO1 – Movement Disorder

Heterozygous de novo variants in GNAO1 are causally associated with early-onset hyperkinetic Movement Disorder. Affected individuals present with dystonia, choreoathetosis, and life-threatening hyperkinetic crises often accompanied by developmental delay, hypotonia, and intellectual disability.

Autosomal dominant inheritance with recurrent de novo missense and splice variants is well documented. Over 30 unrelated probands have been reported with movement phenotypes, including c.709G>A (p.Glu237Lys) (PMID:36247896) and an intronic c.724-8G>A splice variant leading to a two–amino acid insertion (PMID:35147852). Familial mosaic transmission of c.724-8G>A further supports segregation ([PMID:35147852]).

The variant spectrum encompasses >15 missense changes clustering in the switch regions (e.g. p.Gly42Arg, p.Gly203Arg) and several splice-affecting intronic alleles. The c.724-8G>A splice site variant has recurred in ≥4 independent patients with mild developmental delay and dystonia ([PMID:35147852]). No common founder alleles have been identified.

Functional studies reveal that movement disorder-associated variants predominantly exhibit gain-of-function or impaired GTPase activity, resulting in constitutive Gαo activation. In vitro assays show aberrant GTP hydrolysis and disrupted coupling to GPCR effectors correlating with hyperkinetic phenotypes (PMID:28747448).

Animal and cellular models recapitulate key aspects of the human movement phenotype. Gnao1+/R209H knock-in mice display hyperlocomotion reversed by risperidone (PMID:31907305), while C. elegans and Drosophila models exhibit locomotor defects. Rescue of mutant function by zinc supplementation in Drosophila and cell assays further supports targetable pathogenesis (PMID:36206333).

Deep brain stimulation (GPi or STN) provides effective relief for refractory hyperkinetic crises (PMID:35509770). AAV9-mediated intrastriatal delivery of wild-type GNAO1 corrects hyperactivity in R209H mutant mice (PMID:38866563). These convergent lines of evidence support robust diagnostic utility and underpin emerging precision therapeutics. Key Take-home: Genetic testing for GNAO1 variants informs definitive diagnosis and guides targeted treatment in pediatric movement disorders.

References

• Translational Pediatrics • 2022 • Treating GNAO1 mutation-related severe movement disorders with oxcarbazepine: a case report. PMID:36247896
• Neurogenetics • 2022 • An intronic GNAO1 variant leading to in-frame insertion cause movement disorder controlled by deep brain stimulation. PMID:35147852
• Therapeutic Advances in Neurological Disorders • 2022 • Both subthalamic and pallidal deep brain stimulation are effective for GNAO1-associated dystonia: three case reports and a literature review. PMID:35509770
• Movement Disorders • 2017 • Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations. PMID:28747448
• Journal of Pharmacology and Experimental Therapeutics • 2020 • Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone. PMID:31907305
• Science Advances • 2022 • Restoration of the GTPase activity and cellular interactions of Gαo mutants by Zn2+ in GNAO1 encephalopathy models. PMID:36206333
• The Journal of Pharmacology and Experimental Therapeutics • 2024 • AAV9-Mediated Intrastriatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice. PMID:38866563
• Movement Disorders • 2024 • Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. PMID:38881224

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