{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:38:40Z","timestamp":1790818720930,"version":"4.1.0"},"reference-count":13,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2017,3,24]],"date-time":"2017-03-24T00:00:00Z","timestamp":1490313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007786","name":"National Center for Child Health and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007786","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The human genome encodes ~750 G\u2010protein\u2010coupled receptors (<jats:styled-content style=\"fixed-case\">GPCR<\/jats:styled-content>s), including prokineticin receptor 2 (<jats:styled-content style=\"fixed-case\">PROKR<\/jats:styled-content>2) involved in the regulation of sexual maturation. Previously reported pathogenic gain\u2010of\u2010function mutations of <jats:styled-content style=\"fixed-case\">GPCR<\/jats:styled-content> genes invariably encoded aberrant receptors with excessive signal transduction activity. Although <jats:italic>in vitro<\/jats:italic> assays demonstrated that an artificially created inactive mutant of <jats:styled-content style=\"fixed-case\">PROKR<\/jats:styled-content>2 exerted paradoxical gain\u2010of\u2010function effects when co\u2010transfected with wild\u2010type proteins, such a phenomenon has not been observed <jats:italic>in vivo<\/jats:italic>. Here, we report a heterozygous frameshift mutation of <jats:italic><jats:styled-content style=\"fixed-case\">PROKR<\/jats:styled-content>2<\/jats:italic> identified in a 3.5\u2010year\u2010old girl with central precocious puberty. The mutant <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> escaped nonsense\u2010mediated decay and generated a <jats:styled-content style=\"fixed-case\">GPCR<\/jats:styled-content> lacking two transmembrane domains and the carboxyl\u2010terminal tail. The mutant protein had no <jats:italic>in vitro<\/jats:italic> signal transduction activity; however, cells co\u2010expressing the mutant and wild\u2010type <jats:styled-content style=\"fixed-case\">PROKR<\/jats:styled-content>2 exhibited markedly exaggerated ligand\u2010induced Ca<jats:sup>2+<\/jats:sup> responses. The results indicate that certain inactive <jats:styled-content style=\"fixed-case\">PROKR<\/jats:styled-content>2 mutants can cause early puberty by enhancing the functional property of coexisting wild\u2010type proteins. Considering the structural similarity among <jats:styled-content style=\"fixed-case\">GPCR<\/jats:styled-content>s, this paradoxical gain\u2010of\u2010function mechanism may underlie various human disorders.<\/jats:p>","DOI":"10.1111\/jcmm.13146","type":"journal-article","created":{"date-parts":[[2017,3,24]],"date-time":"2017-03-24T16:06:34Z","timestamp":1490371594000},"page":"2623-2626","source":"Crossref","is-referenced-by-count":29,"title":["Paradoxical gain\u2010of\u2010function mutant of the G\u2010protein\u2010coupled receptor <scp>PROKR<\/scp>2 promotes early puberty"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9971-4035","authenticated-orcid":false,"given":"Maki","family":"Fukami","sequence":"first","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erina","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Izumi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Torii","sequence":"additional","affiliation":[{"name":"Department of Pharmacology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Narumi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Igarashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mami","family":"Miyado","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momori","family":"Katsumi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuko","family":"Fujisawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Nakabayashi","sequence":"additional","affiliation":[{"name":"Department of Maternal\u2010Fetal Biology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichiro","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Maternal\u2010Fetal Biology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Umezawa","sequence":"additional","affiliation":[{"name":"Department of Reproductive Biology Center for Regenerative Medicine National Institute for Child Health and Development Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Matsubara","sequence":"additional","affiliation":[{"name":"National Research Institute for Child Health and Development Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"},{"name":"Department of Pediatrics Hamamatsu University School of Medicine Hamamatsu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,3,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2011.20"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.06.022"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa073443"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-2654"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-010-0601-6"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2010-0007"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(02)00546-8"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-243402"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3067"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.04.008"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.05.005"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2014.10.024"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03338"}],"container-title":["Journal 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