Fig. 4. Disease-causing missense mutations of GHRHR.

IGHD refers to conditions of growth hormone deficiency that are not necessarily associated with other pituitary hormone deficiencies or with an organic lesion. While there is no single cause identified for IGHD, defects in growth hormone, GHRHR and GH1 genes are implicated as causative factors⁵⁵. Of which, naturally occurring missense mutations of GHRHR have been studied extensively⁵⁶. a Naturally occurring mutations in the ECD, ligand-binding pocket, and G-protein-coupling region are colored cyan, marine, and magenta, respectively. The central region connecting the ligand-binding pocket and G-protein-coupling region is colored orange. b, c Functional assessment of effects of disease-causing GHRHR mutations on G_s-mediated cAMP accumulation (b) and β-arrestin2 recruitment (c), cAMP accumulation assays and β-arrestin2 recruitment were performed in HEK 293 T cells and data shown are means ± S.E.M. of at least three independent experiments (n = 3–8), performed in quadruplicate or duplicate, respectively. Statistically significant differences were determined with a two-tailed Student’s t test. *P < 0.05, **P < 0.01 vs. wild type (WT); AUC area-under-the-curve. Source data are provided as a Source data file.