Pathogenic Gαo Mutants Drive Dominant GPCR Coupling in GNAO1 Encephalopathies.

ABSTRACT: Heterozygous mutations in GNAO1, which encodes the Gαo subunit of heterotrimeric G proteins, cause a spectrum of neurodevelopmental disorders ranging from early-onset epileptic encephalopathy to dystonia. Although the mechanisms underlying disease dominance remain incompletely understood, some functional disruptions in Gαo mutants have been described. Intriguingly, several Gαo variants have been independently reported to dominantly engage G protein-coupled receptors (GPCRs) or to sequester Gβγ-two seemingly incompatible mechanisms inferred from distinct, indirect biosensor assays. To clarify this apparent contradiction, we developed a split-YFP-based bimolecular fluorescence complementation (BiFC) assay to directly visualize receptor-G_o protein complexes at the plasma membrane.

SUBMITTER: Larasati YA 

PROVIDER: S-EPMC12746902 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature