A mechanistic classification of GNAO1 mutations links Gβγ sequestration to hyperkinetic disease and treatment response
Year: 2026
Type: preprint
Abstract: Gα o is the most prevalent G protein α subunit in the brain and is critical for signal transduction through G protein-coupled receptors. Mutations in the gene encoding Gα o ( GNAO1 ) cause a rare neurodevelopmental disorder with involuntary movements (NEDIM) and, in some patients, developmental and epileptic encephalopathy (DEE). Here, we integrate human genetic analysis with cellular assays to define mechanistic classes of GNAO1 mutations and in vivo approaches to evaluate therapeutic strategies. We grouped variants into two functional categories: those predicted to sequester Gβγ and those with reduced Gα o expression and therefore increased Gβγ signaling. Analysis of patient data revealed that mutations predicted to impair Gβγ release are significantly associated with NEDIM. Using the GNAO1 R209H/+ mouse as a model of NEDIM, we evaluated two small molecules: caffeine, a nonselective adenosine receptor antagonist, and gallein, a selective modulator of Gβγ–effector interactions. Both compounds significantly reduced hyperlocomotion in the open field test. Whole-cell patch-clamp electrophysiology revealed sex- and cell type–specific hyperexcitability in spiny projection neurons within the dorsolateral striatum of GNAO1 R209H/+ mice. Together, these findings implicate dysfunction of dorsolateral striatal pathways in GNAO1-related disorder and suggest that mechanistic understanding of disease variants can guide targeted therapeutic strategies.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7224370436