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

Abstract

BackgroundThe 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.MethodsPrevious 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.Main FindingsOf 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.ConclusionThe 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.

Methylome analysis in girls with idiopathic central precocious puberty

“…GPCRs play particularly important roles in the neurosensory and endocrine systems. The hypothalamic-pituitary–gonadal (HPG) axis in humans comprises at least six GPCRs whose genetic defects, alone or in combination with other gene variants, lead to puberty disorders [ 65 ]. Although alterations in the methylation of GPCR-associated signaling have been reported so far mainly in the development of certain types of tumors [ 66 – 68 ], epigenetic modifications of this pathway could also be linked to normal or early pubertal development [ 69 ].…”

miR-143-3p Promotes Ovarian Granulosa Cell Senescence and Inhibits Estradiol Synthesis by Targeting UBE2E3 and LHCGR

“…Additionally, GCs play a significant role in synthesizing and secreting steroid hormones, which are crucial regulators of reproductive function and under tight control by the hypothalamic–pituitary–gonadal (HPG) axis [ 11 , 12 ]. Receptors in the GCs membrane, including follicle-stimulating hormone receptor (FSHR) and luteinizing hormone/choriogonadotropin receptor (LHCGR), bind to the corresponding pituitary-secreted gonadotropins [ 13 ]. Both FSHR and LHCGR play critical roles in facilitating successful follicular development and ovulation.…”