PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα-protein leads to biased signaling.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disorder caused by the deficient production, secretion, or action of gonadotropin-releasing hormone. Prokineticin (PROK) receptor 2 ( PROKR2), a causative gene for IHH, encodes a GPCR PROKR2. When PROKR2 binds to its ligands PROKs, it may activate several signaling pathways, including IP3/Ca, MAPK, and cAMP pathways. However, the mutational spectrum of PROKR2 in Chinese patients with IHH has not been established. In the present study, we found that up to 13.3% (18/135) of patients with IHH in China carried mutations in PROKR2. Most of the variants in this study were private; however, a PROKR2 (c.533G > C; p.W178S) mutation was identified in 10 independent patients, implying a possible founder mutation. Functional studies indicated that 6 novel PROKR2 mutations led to decreased signaling to various extents. Two IHH-associated mutations (L218P and R270H) disrupted Gαq-dependent signaling but maintained normal Gαs and ERK1/2 signaling. A glutathione S-transferase pull-down experiment demonstrated that R270H mutation disrupted the interaction of intracellular loop 3 of PROKR2 to Gαq protein but not Gαs protein. Our results indicated that selective disruption of the interaction with a specific Gα-protein might underlie the biased signaling for certain IHH-associated PROKR2 mutations.-Zhao, Y., Wu, J., Jia, H., Wang, X., Zheng, R., Jiang, F., Chen, D.-N., Chen, Z., Li, J.-D. PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα-protein leads to biased signaling.