GNAO1 – Developmental and Epileptic Encephalopathy

GNAO1 encodes the Gα₀ subunit of heterotrimeric G proteins and has been established as an autosomal dominant cause of developmental and epileptic encephalopathy (MONDO:0100062). De novo missense and in-frame deletion variants in GNAO1 were first linked to early infantile epileptic encephalopathy-17 (EIEE17) in a cohort of 12 females (12 probands; [PMID:27072799]) and subsequently in four additional unrelated individuals (4 probands; [PMID:25966631]) and one Tunisian case (1 proband; [PMID:37867425]). Functional concordance across studies—ranging from GTPase and cAMP assays to cellular signaling analyses—supports a pathogenic mechanism involving altered nucleotide exchange and G protein–coupled receptor regulation.

Inheritance is strictly autosomal dominant with all reported cases harboring de novo variants. To date, at least 17 de novo missense variants and a single in-frame deletion (p.Leu39del) have been observed in 22 unrelated probands ([PMID:27072799]; [PMID:25966631]; [PMID:37867425]). The variant spectrum is dominated by missense changes clustering at codons Gly203, Arg209, and Glu246, with one recurrent in-frame deletion, and no evidence of familial segregation (affected_relatives = 0).

In vitro functional assays demonstrate both loss-of-function and gain-of-function effects depending on variant: pathogenic alleles impair GTP hydrolysis or accelerate nucleotide exchange, resulting in aberrant modulation of downstream cAMP signaling ([PMID:28747448]). Rescue of GTPase activity by Zn²⁺ supplementation in cell and Drosophila models further confirms the mechanistic impact of these variants ([PMID:36206333]).

Animal and cellular models recapitulate key clinical features. Knock-in mice carrying the G203R allele exhibit both movement abnormalities and enhanced seizure susceptibility ([PMID:30682176]), while C. elegans models of G42R, G203R, and R209C show locomotor defects and dominant-negative behavior ([PMID:34508586]). Ketogenic diet response in one patient and preclinical zinc rescue studies highlight potential therapeutic avenues.

Despite phenotypic overlap with movement disorders, no study refutes the association of GNAO1 with developmental and epileptic encephalopathy. The weight of genetic and experimental evidence supports a definitive pathogenic link. GNAO1 should be included in diagnostic gene panels for early-onset epileptic encephalopathies, and functional assays guide both variant interpretation and therapeutic development.

Key Take-home: De novo autosomal dominant GNAO1 variants are a well-validated cause of developmental and epileptic encephalopathy, with robust genetic and functional evidence informing diagnosis and emerging precision therapies.

References

• Orphanet Journal of Rare Diseases • 2016 • GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females PMID:27072799
• European Journal of Human Genetics • 2016 • Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay PMID:25966631
• Human Molecular Genetics • 2022 • Restoration of the GTPase activity and cellular interactions of Gᵒ mutants by Zn²⁺ in GNAO1 encephalopathy models PMID:36206333
• Neurology • 2017 • Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations PMID:28747448
• PLoS One • 2019 • Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes PMID:30682176
• Journal of Medical Genetics • 2023 • High-throughput sequencing panel for developmental and epileptic encephalopathy in the Tunisian population PMID:37867425

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