{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:27:58Z","timestamp":1790886478483,"version":"4.1.0"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"20","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research of the NIAID","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r\u2212\/\u2212) and its ligand kisspeptin, Kiss1 (Kiss1\u2212\/\u2212) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1\u2212\/\u2212 mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1\u2212\/\u2212 females corrected overtime, hyperaldosteronism persisted at 14\u00a0months and correlated with the overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism [Cushing\u2019s syndrome (CS)] in humans, we sequenced these 2 genes in 65 patients with PA and\/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa215","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T11:22:20Z","timestamp":1601292140000},"page":"3443-3450","source":"Crossref","is-referenced-by-count":8,"title":["Kisspeptin deficiency leads to abnormal adrenal glands and excess steroid hormone secretion"],"prefix":"10.1093","volume":"29","author":[{"given":"Annabel","family":"Berthon","sequence":"first","affiliation":[{"name":"Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA"},{"name":"Institut Cochin, Centre National de la Recherche Scientifique (CNRS), INSERM, Universit\u00e9 Paris Descartes, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Settas","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Delaney","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA"},{"name":"Endocrinology Inter-Institute Training Programs, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Giannakou","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Demidowich","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio R","family":"Faucz","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie B","family":"Seminara","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret E","family":"Chen","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine A","family":"Stratakis","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA"},{"name":"Endocrinology Inter-Institute Training Programs, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,10,21]]},"reference":[{"key":"2021031106310301200_ref1","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1056\/NEJMoa035322","article-title":"The GPR54 gene as a regulator of puberty","volume":"349","author":"Seminara","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"2021031106310301200_ref2","doi-asserted-by":"crossref","first-page":"10714","DOI":"10.1073\/pnas.0704114104","article-title":"Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene","volume":"104","author":"d'Anglemont de Tassigny","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021031106310301200_ref3","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1073\/pnas.0409330102","article-title":"Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54","volume":"102","author":"Messager","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021031106310301200_ref4","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1210\/jc.2017-00763","article-title":"Kisspeptin is a novel regulator of human Fetal adrenocortical development and function: a finding with important implications for the human Fetoplacental unit","volume":"102","author":"Katugampola","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021031106310301200_ref5","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1210\/en.2012-1892","article-title":"Conditional mutagenesis of Gata6 in SF1-positive cells causes gonadal-like differentiation in the adrenal cortex of mice","volume":"154","author":"Pihlajoki","year":"2013","journal-title":"Endocrinology"},{"key":"2021031106310301200_ref6","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1210\/en.2006-1100","article-title":"Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone","volume":"148","author":"Hershkovitz","year":"2007","journal-title":"Endocrinology"},{"key":"2021031106310301200_ref7","doi-asserted-by":"crossref","first-page":"e1000980","DOI":"10.1371\/journal.pgen.1000980","article-title":"Cushing\u2019s syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice","volume":"6","author":"Sahut-Barnola","year":"2010","journal-title":"PLoS Genet."},{"key":"2021031106310301200_ref8","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.1210\/endo.136.11.7588219","article-title":"Developmentally regulated expression of adrenal 17 alpha-hydroxylase cytochrome P450 in the mouse embryo","volume":"136","author":"Keeney","year":"1995","journal-title":"Endocrinology"},{"key":"2021031106310301200_ref9","first-page":"159","article-title":"X-zone degeneration in the adrenal glands of adult and immature female mice","volume":"108","author":"Holmes","year":"1971","journal-title":"J. Anat."},{"key":"2021031106310301200_ref10","doi-asserted-by":"crossref","first-page":"7030","DOI":"10.1128\/MCB.00900-08","article-title":"Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing","volume":"28","author":"Zubair","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2021031106310301200_ref11","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1210\/jc.2009-2421","article-title":"Mutations of the KISS1 gene in disorders of puberty","volume":"95","author":"Silveira","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021031106310301200_ref12","doi-asserted-by":"crossref","first-page":"E1771","DOI":"10.1210\/jc.2011-0518","article-title":"GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1\/Kiss1","volume":"96","author":"Chan","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021031106310301200_ref13","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.mce.2011.12.014","article-title":"DNA polymorphisms of the KiSS1 3\u2019 untranslated region interfere with the folding of a G-rich sequence into G-quadruplex","volume":"351","author":"Huijbregts","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"2021031106310301200_ref14","doi-asserted-by":"crossref","first-page":"15140","DOI":"10.1073\/pnas.1009622107","article-title":"Oligogenic basis of isolated gonadotropin-releasing hormone deficiency","volume":"107","author":"Sykiotis","year":"2010","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2021031106310301200_ref15","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/humrep\/dew073","article-title":"Prevalence of KISS1 receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study","volume":"31","author":"Francou","year":"2016","journal-title":"Hum. Reprod."},{"key":"2021031106310301200_ref16","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.ajhg.2013.04.008","article-title":"Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism","volume":"92","author":"Miraoui","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"2021031106310301200_ref17","article-title":"PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal","volume":"3","author":"Dumontet","year":"2018","journal-title":"JCI Insight"},{"key":"2021031106310301200_ref18","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1177\/1933719107307823","article-title":"Metastin stimulates aldosterone synthesis in human adrenal cells","volume":"14","author":"Nakamura","year":"2007","journal-title":"Reprod. Sci."},{"key":"2021031106310301200_ref19","doi-asserted-by":"crossref","first-page":"5432","DOI":"10.1210\/jc.2005-0963","article-title":"KiSS-1\/G protein-coupled receptor 54 metastasis suppressor pathway increases myocyte-enriched calcineurin interacting protein 1 expression and chronically inhibits calcineurin activity","volume":"90","author":"Stathatos","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021031106310301200_ref20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3389\/fendo.2018.00115","article-title":"Kisspeptin and cancer: molecular interaction, biological functions, and future perspectives","volume":"9","author":"Ciaramella","year":"2018","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"2021031106310301200_ref21","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.metabol.2019.06.007","article-title":"Gonadal hormone-dependent vs. -independent effects of kisspeptin signaling in the control of body weight and metabolic homeostasis","volume":"98","author":"Velasco","year":"2019","journal-title":"Metabolism"},{"key":"2021031106310301200_ref22","doi-asserted-by":"crossref","first-page":"110559","DOI":"10.1016\/j.mce.2019.110559","article-title":"Cre\/lox generation of a novel whole-body Kiss1r KO mouse line recapitulates a hypogonadal, obese, and metabolically-impaired phenotype","volume":"498","author":"Tolson","year":"2019","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021031106310301200_ref23","doi-asserted-by":"crossref","first-page":"110561","DOI":"10.1016\/j.mce.2019.110561","article-title":"Pathological pulses in PCOS","volume":"498","author":"Coyle","year":"2019","journal-title":"Mol. Cell. Endocrinol."},{"key":"2021031106310301200_ref24","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1136\/jmg.2004.028043","article-title":"A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase a develops endocrine and other tumours: comparison with carney complex and other PRKAR1A induced lesions","volume":"41","author":"Griffin","year":"2004","journal-title":"J. Med. Genet."},{"key":"2021031106310301200_ref25","doi-asserted-by":"crossref","first-page":"3495","DOI":"10.1093\/hmg\/ddx235","article-title":"Age-dependent effects of Armc5 haploinsufficiency on adrenocortical function","volume":"26","author":"Berthon","year":"2017","journal-title":"Hum. Mol. Genet."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddaa215\/34447961\/ddaa215.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/20\/3443\/36520879\/ddaa215.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/20\/3443\/36520879\/ddaa215.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T07:14:06Z","timestamp":1615446846000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/29\/20\/3443\/5934549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,15]]},"references-count":25,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10,21]]},"published-print":{"date-parts":[[2020,12,18]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaa215","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,10,15]]},"published":{"date-parts":[[2020,10,15]]}}}