Fig. 4.

GNAS mutational themes in disease. (A) Lollipop plots depict the location of GNAS mutation along the gene body in genetic diseases. Both activating and inactivating mutations are depicted. The height of the lollipop is representative of pathogenic mutation number (ClinVar database) (Landrum et al., 2020). Below the gene body, colored circles depict the location of cancer mutations (COSMIC database) ( Tate et al., 2019). The frequency of residue mutation (residue representing >1% of all GNAS mutations) is shown, with darker blue representing a larger proportion of GNAS mutations occurring at that residue. Hotspot mutations in the switch I and switch II domains are dominant in both genetic diseases and cancer. (B) Structure of the prototypical β₂ adrenergic receptor (β₂AR) coupled to the heterotrimeric Gαs G protein (protein data bank ID: 3SN6). Pathogenic mutations are shown in red spheres. Recurrent mutations are present in the nucleotide binding pocket. Other mutations are present at the receptor–G protein interface and in residues interacting with the Gβγ subunits. (C) Structure of Gαs binding to adenylyl cyclase (PDB: 1AZS) highlights the mutations clustered in the nucleotide binding pocket (switch I and switch II).