Molecular annotation of G protein variants in a neurological disorder

Heterotrimeric G proteins transduce extracellular chemical messages to generate appropriate intracellular responses. Point mutations in GNAO1, encoding the G protein ao subunit, have been implicated in a pathogenic condition characterized by seizures, movement disorders, intellectual disability, and developmental delay (GNAO1 disorder). However, the effects of these mutations on G protein structure and function are unclear. Here, we report the effects of 55 mutations on Gao conformation, thermostability, nucleotide binding, and hydrolysis, as well as interaction with Gbg subunits, receptors, and effectors. Our effort reveals four functionally distinct groups of mutants, including one group that sequesters receptors and another that sequesters Gbg, both acting in a genetically dominant manner. These findings provide a more comprehensive understanding of disease-relevant mutations and reveal that GNAO1 disorder is likely composed of multiple mechanistically distinct disorders that will likely require multiple therapeutic strategies.

Automated summary

In this study, the effects of 55 mutations on G protein structure and function were investigated, revealing four functionally distinct groups of mutants. These findings provide a more comprehensive understanding of disease-relevant mutations and suggest that GNAO1 disorder is composed of multiple mechanistically distinct disorders.