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PROKR2 gene, encoding a G-protein coupled receptor PROKR2, is one of the most frequently mutated genes identified in IHH patients. However, the functional consequences of several PROKR2 mutants remain elusive. In this study, we systematically analyzed the G\u03b1q, G\u03b1s and ERK1\/2 signaling of 23 IHH-associated PROKR2 mutations which are yet to be functionally characterized. We demonstrate that blockage of G\u03b1q, instead of MAPK\/ERK pathway, inhibited PROK2-induced migration of PROKR2-expressing cells, implying that PROKR2-related IHH results primarily due to G\u03b1q signaling pathway disruption. Combined with previous reports, we categorized a total of 63 IHH-associated PROKR2 mutations into four distinct groups according G\u03b1q pathway functionality: (i) neutral (N, &amp;gt;80% activity); (ii) low pathogenicity (L, 50\u201380% activity); (iii) medium pathogenicity (M, 20\u201350% activity) and (iv) high pathogenicity (H, &amp;lt;20% activity). We further compared the cell-based functional results with in silico mutational prediction programs. Our results indicated that while Sorting Intolerant from Tolerant predictions were accurate for transmembrane region mutations, mutations localized in the intracellular and extracellular domains were accurately predicted by the Combined Annotation Dependent Depletion prediction tool. Our results thus provide a functional database that can be used to guide diagnosis and appropriate genetic counseling in IHH patients with PROKR2 mutations.<\/jats:p>","DOI":"10.1093\/hmg\/ddad014","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T02:33:00Z","timestamp":1674613980000},"page":"1722-1729","source":"Crossref","is-referenced-by-count":5,"title":["A functional spectrum of\n                    <i>PROKR2<\/i>\n                    mutations identified in isolated hypogonadotropic hypogonadism"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7491-8194","authenticated-orcid":false,"given":"Xinying","family":"Wang","sequence":"first","affiliation":[{"name":"School of Life Sciences, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Medical Genetics, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Animal Models for Human Diseases, Central South University , Changsha, Hunan 410078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8179-7888","authenticated-orcid":false,"given":"Danna","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Changsha Medical University , Changsha, Hunan 410219 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaguang","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Medical Genetics, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Animal Models for Human Diseases, Central South University , Changsha, Hunan 410078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meichao","family":"Men","sequence":"additional","affiliation":[{"name":"Health Management Center , Xiangya Hospital, , Changsha, Hunan 410078 , China"},{"name":"Central South University , Xiangya Hospital, , Changsha, Hunan 410078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiheng","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Central South University , Changsha, Hunan 410078 , China"},{"name":"Department of Pediatrics , Third Xiangya Hospital, , Changsha, Hunan 410013 , China"},{"name":"Central South University , Third Xiangya Hospital, , Changsha, Hunan 410013 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Medical Genetics, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Animal Models for Human Diseases, Central South University , Changsha, Hunan 410078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The People's Hospital of Henan Province , Zhengzhou, Henan 450003 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria I","family":"Stamou","sequence":"additional","affiliation":[{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital and the Center for Reproductive Medicine , Boston, MA 02141 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey","family":"Plummer","sequence":"additional","affiliation":[{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital and the Center for Reproductive Medicine , Boston, MA 02141 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravikumar","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital and the Center for Reproductive Medicine , Boston, MA 02141 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Da","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Medical Genetics, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan Key Laboratory of Animal Models for Human Diseases, Central South University , Changsha, Hunan 410078 , China"},{"name":"Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Disease , Changsha, Hunan 410078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,25]]},"reference":[{"key":"2023081213415548600_ref1","doi-asserted-by":"crossref","first-page":"147893","DOI":"10.1155\/2012\/147893","article-title":"Genetics of isolated hypogonadotropic hypogonadism: role of 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(Seoul)"},{"issue":"9","key":"2023081213415548600_ref4","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nrendo.2015.112","article-title":"Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment","volume":"11","author":"Boehm","year":"2015","journal-title":"Nat. Rev. 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