Genetic variants of G-protein coupled receptors associated with pubertal disorders

The human hypothalamic-pituitary-gonadal (HPG) axis is the regulatory center for pubertal development. This axis involves six G-protein coupled receptors (GPCRs) encoded by KISS1R, TACR3, PROKR2, GNRHR, LHCGR, and FSHR.

Previous studies have identified several rare variants of the six GPCR genes in patients with pubertal disorders. In vitro assays and animal studies have provided information on the function of wild-type and variant GPCRs.

Of the six GPCRs, those encoded by KISS1R and TACR3 are likely to reside at the top of the HPG axis. Several loss-of-function variants in the six genes were shown to cause late/absent puberty. In particular, variants in KISS1R, TACR3, PROKR2, and GNRHR lead to hypogonadotropic hypogonadism in autosomal dominant, recessive, and oligogenic manners. Furthermore, a few gain-of-function variants of KISS1R, PROKR2, and LHCGR have been implicated in precocious puberty. The human HPG axis may contain additional GPCRs.

The six GPCRs in the HPG axis govern pubertal development through fine-tuning of hormone secretion. Rare sequence variants in these genes jointly account for a certain percentage of genetic causes of pubertal disorders. Still, much remains to be clarified about the molecular network involving the six GPCRs.