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This axis involves six G\u2010protein coupled receptors (GPCRs) encoded by <jats:italic>KISS1R<\/jats:italic>, <jats:italic>TACR3<\/jats:italic>, <jats:italic>PROKR2<\/jats:italic>, <jats:italic>GNRHR<\/jats:italic>, <jats:italic>LHCGR<\/jats:italic>, and <jats:italic>FSHR<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010type and variant GPCRs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Findings<\/jats:title><jats:p>Of the six GPCRs, those encoded by <jats:italic>KISS1R<\/jats:italic> and <jats:italic>TACR3<\/jats:italic> are likely to reside at the top of the HPG axis. Several loss\u2010of\u2010function variants in the six genes were shown to cause late\/absent puberty. In particular, variants in <jats:italic>KISS1R<\/jats:italic>, <jats:italic>TACR3<\/jats:italic>, <jats:italic>PROKR2<\/jats:italic>, and <jats:italic>GNRHR<\/jats:italic> lead to hypogonadotropic hypogonadism in autosomal dominant, recessive, and oligogenic manners. Furthermore, a few gain\u2010of\u2010function variants of <jats:italic>KISS1R<\/jats:italic>, <jats:italic>PROKR2<\/jats:italic>, and <jats:italic>LHCGR<\/jats:italic> have been implicated in precocious puberty. The human HPG axis may contain additional GPCRs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The six GPCRs in the HPG axis govern pubertal development through fine\u2010tuning 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/rmb2.12515","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T11:34:15Z","timestamp":1682595255000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genetic variants of G\u2010protein coupled receptors associated with pubertal disorders"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5165-2007","authenticated-orcid":false,"given":"Erina","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo 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