{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T23:56:03Z","timestamp":1772150163709,"version":"3.50.1"},"reference-count":33,"publisher":"The Endocrine Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,3,1]]},"abstract":"<jats:sec>\n                  <jats:title>Context:<\/jats:title>\n                  <jats:p>Loss of prokineticin 2 (PROK2) signaling in mice disrupts circadian rhythms, but the role of PROK2 signaling in the regulation of circadian rhythms in humans is undetermined.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>The aim of the study was to examine the circadian rhythms of humans with a complete loss-of-function PROK2 mutation using an inpatient constant routine (CR) protocol.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design and Setting:<\/jats:title>\n                  <jats:p>We conducted a case study in an academic medical center.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Subjects and Methods:<\/jats:title>\n                  <jats:p>Two siblings (one male and one female, ages 67 and 62 y, respectively) with isolated GnRH deficiency (IGD) due to a biallelic loss-of-function PROK2 mutation were studied using an inpatient CR protocol. Historical data from inpatient CR protocols conducted in healthy controls (ages 65\u201381 y) were used for comparison.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Main Outcome Measures:<\/jats:title>\n                  <jats:p>We measured circadian phase markers (melatonin, cortisol, and core body temperature) and neurobehavioral performance (psychomotor vigilance task [PVT] and subjective alertness scale).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>Circadian waveforms of melatonin and cortisol did not differ between the IGD participants with PROK2 mutation and controls. In both IGD participants, neurobehavioral testing with PVT showed disproportionate worsening of PVT lapses and median reaction time in the second half of the CR.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>Humans with loss of PROK2 signaling lack abnormalities in circadian phase markers, indicating intact central circadian pacemaker activity in these patients. These results suggest that PROK2 signaling in humans is not required for central circadian pacemaker function. However, impaired PVT in the PROK2-null participants despite preserved endocrine rhythms suggests that PROK2 may transmit circadian timing information to some neurobehavioral neural networks.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2013-2096","type":"journal-article","created":{"date-parts":[[2014,1,14]],"date-time":"2014-01-14T10:06:36Z","timestamp":1389693996000},"page":"E561-E566","source":"Crossref","is-referenced-by-count":9,"title":["Absence of Central Circadian Pacemaker Abnormalities in Humans With Loss of Function Mutation in Prokineticin 2"],"prefix":"10.1210","volume":"99","author":[{"given":"Ravikumar","family":"Balasubramanian","sequence":"first","affiliation":[{"name":"Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine (R.B., J.E.H., A.A.D., N.P., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114"}]},{"given":"Daniel A.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Division of Sleep Medicine (D.A.C., E.B.K., C.A.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115"}]},{"given":"Elizabeth B.","family":"Klerman","sequence":"additional","affiliation":[{"name":"Division of Sleep Medicine (D.A.C., E.B.K., C.A.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115"}]},{"given":"Duarte","family":"Pignatelli","sequence":"additional","affiliation":[{"name":"Department of Endocrinology-Hospital S\u00e3o Jo\u00e3o (D.P.), 4200\u2013319 Porto, Portugal"},{"name":"Department of Experimental Biology-Faculty of Medicine (D.P.), 4200\u2013319 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology at the University of Porto (IPATIMUP) (D.P.), 4200\u2013319 Porto, Portugal"}]},{"given":"Janet E.","family":"Hall","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine (R.B., J.E.H., A.A.D., N.P., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114"}]},{"given":"Andrew A.","family":"Dwyer","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine (R.B., J.E.H., A.A.D., N.P., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114"}]},{"given":"Charles A.","family":"Czeisler","sequence":"additional","affiliation":[{"name":"Division of Sleep Medicine (D.A.C., E.B.K., C.A.C.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115"}]},{"given":"Nelly","family":"Pitteloud","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine (R.B., J.E.H., A.A.D., N.P., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114"}]},{"given":"William F.","family":"Crowley","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine (R.B., J.E.H., A.A.D., N.P., W.F.C.), Massachusetts General Hospital, Boston, Massachusetts 02114"}]}],"member":"80","reference":[{"key":"2020071613402810800_B1","first-page":"97","article-title":"Circadian and sleep-dependent regulation of hormone release in humans","volume":"54","author":"Czeisler","year":"1999","journal-title":"Recent Prog Horm Res"},{"key":"2020071613402810800_B2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1530\/rep.1.00614","article-title":"Circadian rhythms and reproduction","volume":"132","author":"Boden","year":"2006","journal-title":"Reproduction"},{"key":"2020071613402810800_B3","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/B978-0-12-387690-4.00006-4","article-title":"Genetics of circadian rhythms in mammalian model organisms","volume":"74","author":"Lowrey","year":"2011","journal-title":"Adv Genet"},{"key":"2020071613402810800_B4","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/nature04284","article-title":"Hypothalamic regulation of sleep and circadian rhythms","volume":"437","author":"Saper","year":"2005","journal-title":"Nature"},{"key":"2020071613402810800_B5","doi-asserted-by":"crossref","first-page":"11615","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":"2020071613402810800_B6","doi-asserted-by":"crossref","first-page":"405","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":"2020071613402810800_B7","first-page":"247","article-title":"Altered circadian and homeostatic sleep regulation in prokineticin 2-deficient mice","volume":"30","author":"Hu","year":"2007","journal-title":"Sleep"},{"key":"2020071613402810800_B8","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1073\/pnas.0606884104","article-title":"Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei","volume":"104","author":"Prosser","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613402810800_B9","doi-asserted-by":"crossref","first-page":"e20263","DOI":"10.1371\/journal.pone.0020263","article-title":"Prokineticin 2 regulates the electrical activity of rat suprachiasmatic nuclei neurons","volume":"6","author":"Ren","year":"2011","journal-title":"PLoS One"},{"key":"2020071613402810800_B10","doi-asserted-by":"crossref","first-page":"e7151","DOI":"10.1371\/journal.pone.0007151","article-title":"Efferent projections of prokineticin 2 expressing neurons in the mouse suprachiasmatic nucleus","volume":"4","author":"Zhang","year":"2009","journal-title":"PLoS One"},{"key":"2020071613402810800_B11","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/j.1460-9568.2006.05293.x","article-title":"Prokineticin 2 depolarizes paraventricular nucleus magnocellular and parvocellular neurons","volume":"25","author":"Yuill","year":"2007","journal-title":"Eur J Neurosci"},{"key":"2020071613402810800_B12","doi-asserted-by":"crossref","first-page":"17447","DOI":"10.1073\/pnas.0707173104","article-title":"Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism","volume":"104","author":"Pitteloud","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613402810800_B13","doi-asserted-by":"crossref","first-page":"4140","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":"Proc Natl Acad Sci USA"},{"key":"2020071613402810800_B14","doi-asserted-by":"crossref","first-page":"e175","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":"2020071613402810800_B15","doi-asserted-by":"crossref","first-page":"3551","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":"2020071613402810800_B16","doi-asserted-by":"crossref","first-page":"225","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":"2011","journal-title":"Endocr Rev"},{"key":"2020071613402810800_B17","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1177\/074873002129002294","article-title":"Getting through to circadian oscillators: why use constant routines?","volume":"17","author":"Duffy","year":"2002","journal-title":"J Biol Rhythms"},{"key":"2020071613402810800_B18","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.2044-8341.1974.tb02285.x","article-title":"The use of analogue scales in rating subjective feelings","volume":"47","author":"Bond","year":"1974","journal-title":"Br J Med Psychol"},{"key":"2020071613402810800_B19","first-page":"512","article-title":"Circadian rhythm in indices of human performance, physical fitness and stress resistance","volume":"39","author":"Klein","year":"1968","journal-title":"Aerosp Med"},{"key":"2020071613402810800_B20","doi-asserted-by":"crossref","first-page":"652","DOI":"10.3758\/BF03200977","article-title":"Microcomputer analyses of performance on a portable, simple visual RT task during sustained operations","volume":"17","author":"Dinges","year":"1985","journal-title":"Behav Res Methods Instrum Comput"},{"key":"2020071613402810800_B21","volume-title":"A Manual of Standardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects","author":"Rechtschaffen","year":"1968"},{"key":"2020071613402810800_B22","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1177\/074873002129002474","article-title":"Comparisons of the variability of three markers of the human circadian pacemaker","volume":"17","author":"Klerman","year":"2002","journal-title":"J Biol Rhythms"},{"key":"2020071613402810800_B23","doi-asserted-by":"crossref","first-page":"30","DOI":"10.2310\/6650.2001.34088","article-title":"Circadian phase resetting in older people by ocular bright light exposure","volume":"49","author":"Klerman","year":"2001","journal-title":"J Investig Med"},{"key":"2020071613402810800_B24","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.cub.2008.06.047","article-title":"Age-related reduction in the maximal capacity for sleep\u2014implications for insomnia","volume":"18","author":"Klerman","year":"2008","journal-title":"Curr Biol"},{"key":"2020071613402810800_B25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1177\/074873049200700301","article-title":"The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data","volume":"7","author":"Brown","year":"1992","journal-title":"J Biol Rhythms"},{"key":"2020071613402810800_B26","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1126\/science.284.5423.2177","article-title":"Stability, precision, and near-24-hour period of the human circadian pacemaker","volume":"284","author":"Czeisler","year":"1999","journal-title":"Science"},{"key":"2020071613402810800_B27","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.expneurol.2012.07.012","article-title":"Genetic basis of human circadian rhythm disorders","volume":"243","author":"Jones","year":"2013","journal-title":"Exp Neurol"},{"key":"2020071613402810800_B28","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/B978-0-12-387690-4.00007-6","article-title":"The genetics of the human circadian clock","volume":"74","author":"Zhang","year":"2011","journal-title":"Adv Genet"},{"key":"2020071613402810800_B29","doi-asserted-by":"crossref","first-page":"e52","DOI":"10.1371\/journal.pbio.1000052","article-title":"Network features of the mammalian circadian clock","volume":"7","author":"Baggs","year":"2009","journal-title":"PLoS Biol"},{"key":"2020071613402810800_B30","doi-asserted-by":"crossref","first-page":"659","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":"2020071613402810800_B31","doi-asserted-by":"crossref","first-page":"14ra13","DOI":"10.1126\/scitranslmed.3000458","article-title":"Uncovering residual effects of chronic sleep loss on human performance","volume":"2","author":"Cohen","year":"2010","journal-title":"Sci Transl Med"},{"key":"2020071613402810800_B32","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1001\/jama.294.9.1025","article-title":"Neurobehavioral performance of residents after heavy night call vs after alcohol ingestion","volume":"294","author":"Arnedt","year":"2005","journal-title":"JAMA"},{"key":"2020071613402810800_B33","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1523\/JNEUROSCI.15-05-03526.1995","article-title":"Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans","volume":"15","author":"Dijk","year":"1995","journal-title":"J Neurosci"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/99\/3\/E561\/11158214\/jcemE561.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/99\/3\/E561\/11158214\/jcemE561.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:22:34Z","timestamp":1594945354000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/99\/3\/E561\/2537348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,1]]},"references-count":33,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014,3,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2013-2096","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3,1]]}}}