{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:12:29Z","timestamp":1790356349690,"version":"4.1.0"},"reference-count":36,"publisher":"The Endocrine Society","issue":"12","license":[{"start":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T00:00:00Z","timestamp":1687219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche\/voice-breaking in the UK Biobank cohort.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8\/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4\/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged \u226516 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgad373","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T19:29:14Z","timestamp":1687289354000},"page":"e1580-e1587","source":"Crossref","is-referenced-by-count":17,"title":["Prevalence of Deleterious Variants in <i>MC3R<\/i> in Patients With Constitutional Delay of Growth and Puberty"],"prefix":"10.1210","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0222-1689","authenticated-orcid":false,"given":"Katie","family":"Duckett","sequence":"first","affiliation":[{"name":"Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke\u2019s Hospital , Cambridge CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7599-9301","authenticated-orcid":false,"given":"Alice","family":"Williamson","sequence":"additional","affiliation":[{"name":"Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke\u2019s Hospital , Cambridge CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0660-9813","authenticated-orcid":false,"given":"John W R","family":"Kincaid","sequence":"additional","affiliation":[{"name":"Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke\u2019s Hospital , Cambridge CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8089-0693","authenticated-orcid":false,"given":"Kara","family":"Rainbow","sequence":"additional","affiliation":[{"name":"Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke\u2019s Hospital , Cambridge CB2 0QQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4032-9500","authenticated-orcid":false,"given":"Laura J","family":"Corbin","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol , Oakfield House, Oakfield Grove, Bristol BS8 2BN , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-9084","authenticated-orcid":false,"given":"Hilary C","family":"Martin","sequence":"additional","affiliation":[{"name":"Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus , Hinxton, Cambridge CB10 1SA , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6152-1369","authenticated-orcid":false,"given":"Ruth Y","family":"Eberhardt","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus , Hinxton, Cambridge CB10 1SA , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3073-717X","authenticated-orcid":false,"given":"Qin Qin","family":"Huang","sequence":"additional","affiliation":[{"name":"Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus , Hinxton, Cambridge CB10 1SA , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2333-7015","authenticated-orcid":false,"given":"Matthew E","family":"Hurles","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus , Hinxton, Cambridge CB10 1SA , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"He","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Pediatrics, Boston Children\u2019s Hospital , 300 Longwood Ave, Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4456-4508","authenticated-orcid":false,"given":"Raja","family":"Brauner","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Unit, H\u00f4pital Fondation Adolphe de Rothschild and Universit\u00e9 Paris Cit\u00e9 , 25 rue Manin, 75019 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0632-6365","authenticated-orcid":false,"given":"Angela","family":"Delaney","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children\u2019s Research Hospital , 262 Danny Thomas Place MS 737, Memphis, TN 38105 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Dunkel","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts & the London Medical School , Charterhouse Square, London EC1M 6BQ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-1518","authenticated-orcid":false,"given":"Romina P","family":"Grinspon","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Endocrinol\u00e8gicas \u201cDr. C\u00e9sar Bergad\u00e1\u201d (CEDIE), CONICET\u2013FEI\u2013Divisi\u00e8n de Endocrinolog\u00eda, Hospital de Ni\u00f1os Ricardo Guti\u00e9rrez , Gallo 1330, C1425EFD Buenos Aires , Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4644-3061","authenticated-orcid":false,"given":"Janet E","family":"Hall","sequence":"additional","affiliation":[{"name":"Clinical Research 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M\u00e9dica , Av. Dr. Arnaldo, 455 - Cerqueira C\u00e9sar, 01246903 S\u00e3o Paulo - SP , Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A L","family":"Jorge","sequence":"additional","affiliation":[{"name":"Departamento de Cl\u00ednica M\u00e9dica , Av. 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