{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:40:44Z","timestamp":1793320844023,"version":"4.5.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Prokineticin receptor 2 (<jats:italic>PROKR2<\/jats:italic>) encodes for a G-protein-coupled receptor that can bind PROK1 and PROK2. Mice lacking <jats:italic>Prokr2<\/jats:italic> have been shown to present abnormal olfactory bulb formation as well as defects in GnRH neuron migration. Patients carrying mutations in <jats:italic>PROKR2<\/jats:italic> typically present hypogonadotropic hypogonadism, anosmia\/hyposmia or Kallmann Syndrome. More recently variants in <jats:italic>PROKR2<\/jats:italic> have been linked to several other endocrine disorders. In particular, several patients with pituitary disorders have been reported, ranging from mild phenotypes, such as isolated growth hormone deficiency, to more severe ones, such as septo-optic dysplasia. Here we summarize the changing landscape of <jats:italic>PROKR2<\/jats:italic>-related disease, the variants reported to date, and discuss their origin, classification and functional assessment.<\/jats:p>","DOI":"10.3389\/fendo.2023.1132787","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T04:33:07Z","timestamp":1675830787000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Phenotypic and genotypic landscape of PROKR2 in neuroendocrine disorders"],"prefix":"10.3389","volume":"14","author":[{"given":"Julian","family":"Martinez-Mayer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Ines","family":"Perez-Millan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2008.61","article-title":"Disruption of the circadian output molecule prokineticin 2 results in anxiolytic and antidepressant-like effects in mice","volume":"34","author":"Li","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.4.692","article-title":"Identification of two prokineticin cDNAs: Recombinant proteins potently contract gastrointestinal smooth muscle","volume":"59","author":"Li","year":"2001","journal-title":"Mol Pharmacol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2010.06.011","article-title":"Prokineticins in angiogenesis and cancer","volume":"296","author":"Monnier","year":"2010","journal-title":"Cancer Lett"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1112103","article-title":"Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling","volume":"308","author":"Ng","year":"2005","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","first-page":"397","DOI":"10.2337\/db09-1198","article-title":"Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake","volume":"59","author":"Gardiner","year":"2009","journal-title":"Diabetes"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/417405a","article-title":"Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus","volume":"417","author":"Cheng","year":"2002","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3679-06.2006","article-title":"Attenuated circadian rhythms in mice lacking the prokineticin 2 gene","volume":"26","author":"Li","year":"2006","journal-title":"J Neurosci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508881103","article-title":"Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2","volume":"103","author":"Matsumoto","year":"2006","journal-title":"PNAS"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0020175","article-title":"Kallmann syndrome: Mutations in the genes encoding prokineticin-2 and prokineticin receptor-2","volume":"2","author":"Dod\u00e9","year":"2006","journal-title":"PLoS Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2021.111489","article-title":"Next-generation sequencing-based mutational analysis of idiopathic short stature and isolated growth hormone deficiency in Korean pediatric patients","volume":"544","author":"Ahn","year":"2022","journal-title":"Mol Cell Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cca.2021.11.021","article-title":"Molecular diagnosis for growth hormone deficiency in Chinese children and adolescents and evaluation of impact of rare genetic variants on treatment efficacy of growth hormone","volume":"524","author":"He","year":"2022","journal-title":"Clinica Chimica Acta"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38306","article-title":"A heterozygous microdeletion of 20p12.2-3 encompassingPROKR2andBMP2in a patient with congenital hypopituitarism and growth hormone deficiency","volume":"173","author":"Parsons","year":"2017","journal-title":"Am J Med Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3067","article-title":"Variations inPROKR2, but NotPROK2, are associated with hypopituitarism and septo-optic dysplasia","volume":"98","author":"McCabe","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-3056","article-title":"PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption","volume":"97","author":"Reynaud","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14355","article-title":"Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort","volume":"94","author":"Jullien","year":"2020","journal-title":"Clin Endocrinol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-00332","article-title":"Digenic inheritance of PROKR2 and WDR11 mutations in pituitary stalk interruption syndrome","volume":"102","author":"McCormack","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2938","article-title":"Genetic overlap in kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia","volume":"97","author":"Raivio","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13146","article-title":"Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty","volume":"21","author":"Fukami","year":"2017","journal-title":"J Cell Mol Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-0843","article-title":"A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes","volume":"95","author":"Sarfati","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.2017.S010","article-title":"Update on the genetics of idiopathic hypogonadotropic hypogonadism","volume":"9","author":"Topalo\u011flu","year":"2018","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx404","article-title":"Modeling mutant\/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency","volume":"27","author":"Cox","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-017-0014-1","article-title":"Next-generation sequencing of patients with congenital anosmia","volume":"25","author":"Alkelai","year":"2017","journal-title":"Eur J Hum Genet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1177\/1535370215587531","article-title":"Mutation analyses in pedigrees and sporadic cases of ethnic han Chinese kallmann syndrome patients","volume":"240","author":"Gu","year":"2015","journal-title":"Exp Biol Med (Maywood)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-12-0578","article-title":"PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency","volume":"168","author":"Moya-Plana","year":"2013","journal-title":"Eur J Endocrinol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/cne.24719","article-title":"The PROK2\/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons","volume":"527","author":"Wen","year":"2019","journal-title":"J Comp Neurol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13052-020-00951-z","article-title":"Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty","volume":"47","author":"Aiello","year":"2021","journal-title":"Ital J Pediatr"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0958","article-title":"Loss-of-Function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive kallmann syndrome","volume":"93","author":"Abreu","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4116","article-title":"Prioritizing genetic testing in patients with kallmann syndrome using clinical phenotypes","volume":"98","author":"Costa-Barbosa","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-021-00609-z","article-title":"Comparison of clinical characteristics and spermatogenesis in CHH patients caused by PROKR2 and FGFR1 mutations","volume":"28","author":"Li","year":"2021","journal-title":"Reprod Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-2654","article-title":"Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: Molecular genetics and clinical spectrum","volume":"93","author":"Cole","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh309","article-title":"The product of X-linked kallmann\u2019s syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons","volume":"13","author":"Cariboni","year":"2004","journal-title":"Hum Mol Genet"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22179425","article-title":"The differential roles for neurodevelopmental and neuroendocrine genes in shaping GnRH neuron physiology and deficiency","volume":"22","author":"Oleari","year":"2021","journal-title":"IJMS"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/ng1407","article-title":"Mutations in a new member of the chromodomain gene family cause CHARGE syndrome","volume":"36","author":"Vissers","year":"2004","journal-title":"Nat Genet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp112","article-title":"Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome","volume":"18","author":"Layman","year":"2009","journal-title":"Hum Mol Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy045","article-title":"Sema3a plays a role in the pathogenesis of CHARGE syndrome","volume":"27","author":"Ufartes","year":"2018","journal-title":"Hum Mol Genet"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00368","article-title":"SEMA3A and IGSF10 are novel contributors to combined pituitary hormone deficiency (CPHD)","volume":"11","author":"Budny","year":"2020","journal-title":"Front Endocrinol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.846801","article-title":"Correlation analysis of genotypes and phenotypes in Chinese Male pediatric patients with congenital hypogonadotropic hypogonadism","volume":"13","author":"Wang","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/and.14583","article-title":"Reversal of idiopathic hypogonadotropic hypogonadism in a Chinese male cohort","volume":"54","author":"Sun","year":"2022","journal-title":"Andrologia"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ21-0779","article-title":"Biallelic PROKR2 variants and congenital hypogonadotropic hypogonadism: a case report and a literature review","volume":"69","author":"Sugisawa","year":"2022","journal-title":"Endocr J"},{"key":"B41","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12902-022-00940-9","article-title":"Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism","volume":"22","author":"Liu","year":"2022","journal-title":"BMC Endocr Disord"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsxm.2021.07.001","article-title":"Genetic profiles and three-year follow-up study of Chinese males with congenital hypogonadotropic hypogonadism","volume":"18","author":"Zhang","year":"2021","journal-title":"J Sexual Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"288","DOI":"10.4103\/aja.aja_65_20","article-title":"Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism","volume":"23","author":"Tang","year":"2021","journal-title":"Asian J Androl"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201801575R","article-title":"PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: Selective disruption of the binding to aG\u03b1-protein leads to biased signaling","volume":"33","author":"Zhao","year":"2018","journal-title":"FASEB J"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1055\/a-0681-6608","article-title":"Targeted gene panel sequencing for molecular diagnosis of kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism","volume":"127","author":"Kim","year":"2018","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"B46","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.fertnstert.2018.04.010","article-title":"Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism","volume":"110","author":"Zhou","year":"2018","journal-title":"Fertility Sterility"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13451","article-title":"Clinical and genetic features of 64 young male paediatric patients with congenital hypogonadotropic hypogonadism","volume":"87","author":"Wang","year":"2017","journal-title":"Clin Endocrinol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e7974","DOI":"10.1097\/MD.0000000000007974","article-title":"Kallmann syndrome with a Tyr113His PROKR2 mutation","volume":"96","author":"Ha","year":"2017","journal-title":"Medicine"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-2292","article-title":"Expanding the phenotype and genotype of female GnRH deficiency","volume":"96","author":"Shaw","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-020-00654-8","article-title":"Identification of MMACHC and PROKR2 mutations causing coexistent cobalamin c disease and kallmann syndrome in a young woman","volume":"36","author":"Yuan","year":"2021","journal-title":"Metab Brain Dis"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1111\/and.13594","article-title":"Identification of two novel mutations in three Chinese families with kallmann syndrome using whole exome sequencing","volume":"52","author":"Zhang","year":"2020","journal-title":"Andrologia"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.4000\/eps.3657","article-title":"Mariages \u00abmixtes\u00bb et immigration en France","author":"Tribalat","year":"2009","journal-title":"Eps"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2431","article-title":"Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differential modulation of distinct intracellular pathways","volume":"99","author":"Libri","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1064-z","article-title":"Genetic compensation triggered by mutant mRNA degradation","volume":"568","author":"El-Brolosy","year":"2019","journal-title":"Nature"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1210\/er.2010-0007","article-title":"The role of the prokineticin 2 pathway in human reproduction: Evidence from the study of human and murine gene mutations","volume":"32","author":"Martin","year":"2010","journal-title":"Endocrine Rev"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1210\/me.2012-1102","article-title":"Evidence of the importance of the first intracellular loop of prokineticin receptor 2 in receptor function","volume":"26","author":"Abreu","year":"2012","journal-title":"Mol Endocrinol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-243402","article-title":"Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations","volume":"28","author":"Sbai","year":"2014","journal-title":"FASEB J"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.08.039","article-title":"Functional analysis of the distal region of the third intracellular loop of PROKR2","volume":"439","author":"Zhou","year":"2013","journal-title":"Biochem Biophys Res Commun"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.223784","article-title":"Disease-causing mutation in PKR2 receptor reveals a critical role of positive charges in the second intracellular loop for G-protein coupling and receptor trafficking","volume":"286","author":"Peng","year":"2011","journal-title":"J Biol Chem"},{"key":"B60","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1093\/hmg\/ddn318","article-title":"PROKR2 missense mutations associated with kallmann syndrome impair receptor signalling activity","volume":"18","author":"Monnier","year":"2008","journal-title":"Hum Mol Genet"},{"key":"B61","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1530\/REP-13-0043","article-title":"Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy","volume":"146","author":"Su","year":"2013","journal-title":"Reproduction"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-011-9245-8","article-title":"Innovative functional cAMP assay for studying G protein-coupled receptors: application to the pharmacological characterization of GPR17","volume":"7","author":"Buccioni","year":"2011","journal-title":"Purinergic Signalling"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.556381","article-title":"Functional rescue of kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking","volume":"289","author":"Chen","year":"2014","journal-title":"J Biol Chem"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds264","article-title":"An ancient founder mutation in PROKR2 impairs human reproduction","volume":"21","author":"Avbelj Stefanija","year":"2012","journal-title":"Hum Mol Genet"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1132787\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T04:33:09Z","timestamp":1675830789000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1132787\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,8]]},"references-count":64,"alternative-id":["10.3389\/fendo.2023.1132787"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1132787","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,8]]},"article-number":"1132787"}}