Sci Signal 2025 Dec 02;18915:eadt8890. doi: 10.1126/scisignal.adt8890.

GNAI1 missense mutations associated with a neurodevelopmental syndrome modify Gαi1 function.

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G protein-coupled receptors (GPCRs) play key roles in neurodevelopment by regulating excitatory and inhibitory neuronal pathways. The G protein subunit Gαi1 is a downstream effector of inhibitory GPCR signaling, and the gene encoding it (GNAI1) is abundantly expressed in the brain. Rare GNAI1 variants are linked to a severe neurodevelopmental disorder called GNAI1 syndrome, which is characterized by intellectual disability, a range of movement issues, and epilepsy. Here, we investigated the effect of five GNAI1 syndrome-associated missense variants on GPCR signaling. Predictions based on genetic biobank data and in silico modeling suggested that these variants were pathogenic. Compared with the wild-type protein, four Gαi1 variants (T48K, T48I, C224Y, and V332E) showed marked increases in dopamine potency at the dopamine D2 receptor (D2R) and increased constitutive G protein activity when expressed in Xenopus laevis oocytes. By contrast, the Gαi1 G40C variant was unresponsive to D2R activation. All Gαi1 variants displayed reduced GTP-γ-S binding rates and undetectable GTP hydrolysis, except for the T48I variant, which showed more rapid binding and hydrolysis. Thus, four GNAI1 syndrome variants caused a net gain-of-function effect on D2R signaling, and all studied variants disrupted GTP exchange. These biochemical effects may underlie GNAI1 syndrome, and GNAI1 mutations should therefore be considered when screening for rare neurodevelopmental disorders.

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