Functional classification of GNAI1 disorder variants in Caenorhabditis elegans uncovers conserved and cell-specific mechanisms of dysfunction.

ABSTRACT: Heterotrimeric G proteins transduce signals from G protein-coupled receptors, which mediate key aspects of neuronal development and function. Mutations in the GNAI1 gene, which encodes Gαi1, cause a disorder characterized by developmental delay, intellectual disability, hypotonia, and epilepsy. However, the mechanistic basis for this disorder remains unknown. Here, we show that GNAI1 is required for ciliogenesis in human cells and use Caenorhabditis elegans as a whole-organism model to determine the functional impact of 7 GNAI1-disorder patient variants. Using CRISPR-Cas9 editing in combination with robust cellular (cilia morphology) and behavioral (chemotaxis) assays, we find that T48I, K272R, A328P, and V334E orthologous variants impact both cilia assembly and function in AWC neurons, M8

SUBMITTER: Salama R 

PROVIDER: S-EPMC12693566 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature