Dominant Gα mutations in human disease: unifying mechanisms and treatment strategies

Sixteen Gα-subunits transduce hundreds of G protein-coupled receptors and control countless cellular activities. Mutations in respective GNA genes underlie developmental, oncological, metabolic, neurological, and other pathologies. In addition to classical loss-of-function (LOF) and gain-of-function (GOF) mutations (the former represented by gene deletions/truncations, the latter by specific GTP hydrolysis-deficient mutations), multiple pathogenic dominant missense variants have been discovered in GNA genes, and their numbers constantly increase through advanced genetic diagnostics. While these mutations often have confusing features of hypomorphic, dominant-negative, and GOF mutations, many of the pathogenic Gαo (and by inference, other Gα-subunit) variants have recently emerged as neomorphic, i.e., leading to the creation of novel dominant pathogenic functions. Cross-family analysis of these missense variants scattered across GNA genes permits establishing mutational signatures underlying a wide range of Gα-pathies. These mutation patterns have a strong predictive power in the following aspects. First, new dominant mutations in further GNA genes will be discovered in rare diseases. Second, unifying mechanisms of pathogenic dominance emerge in different Gα-subunits. And third, drug(s) acting against some Gα-pathies may prove effective against others.