{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T06:14:58Z","timestamp":1767852898738,"version":"3.49.0"},"reference-count":28,"publisher":"Proceedings of the National Academy of Sciences","issue":"44","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,10,30]]},"abstract":"<jats:p>\n            Gonadotropin-releasing hormone (GnRH) deficiency in the human presents either as normosmic idiopathic hypogonadotropic hypogonadism (nIHH) or with anosmia [Kallmann syndrome (KS)]. To date, several loci have been identified to cause these disorders, but only 30% of cases exhibit mutations in known genes. Recently, murine studies have demonstrated a critical role of the prokineticin pathway in olfactory bulb morphogenesis and GnRH secretion. Therefore, we hypothesize that mutations in\n            <jats:italic>prokineticin 2<\/jats:italic>\n            (\n            <jats:italic>PROK2<\/jats:italic>\n            ) underlie some cases of KS in humans and that animals deficient in\n            <jats:italic>Prok2<\/jats:italic>\n            would be hypogonadotropic. One hundred IHH probands (50 nIHH and 50 KS) with no known mutations were examined for mutations in the\n            <jats:italic>PROK2<\/jats:italic>\n            gene. Mutant PROK2s were examined in functional studies, and the reproductive phenotype of the\n            <jats:italic>Prok2<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice was also investigated. Two brothers with KS and their sister with nIHH harbored a homozygous deletion in the\n            <jats:italic>PROK2<\/jats:italic>\n            gene (p.[I55fsX1]+[I55fsX1]). Another asymptomatic brother was heterozygous for the deletion, whereas both parents (deceased) had normal reproductive histories. The identified deletion results in a truncated PROK2 protein of 27 amino acids (rather than 81 in its mature form) that lacks bioactivity. In addition,\n            <jats:italic>Prok2<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice with olfactory bulb defects exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism. Homozygous loss-of-function\n            <jats:italic>PROK2<\/jats:italic>\n            mutations cause both KS and nIHH.\n          <\/jats:p>","DOI":"10.1073\/pnas.0707173104","type":"journal-article","created":{"date-parts":[[2007,10,24]],"date-time":"2007-10-24T23:20:39Z","timestamp":1193268039000},"page":"17447-17452","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":223,"title":["Loss-of-function mutation in the\n            <i>prokineticin 2<\/i>\n            gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism"],"prefix":"10.1073","volume":"104","author":[{"given":"Nelly","family":"Pitteloud","sequence":"first","affiliation":[{"name":"*Reproductive Endocrine Unit, Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, MA 02114;"}]},{"given":"Chengkang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Irvine, CA 92697;"}]},{"given":"Duarte","family":"Pignatelli","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Laboratory of Cellular and Molecular Biology, Institute of Molecular Pathology and Immunology, University of Porto, San Jo\u00e3o Hospital, 4200-465 Porto, Portugal; and"}]},{"given":"Jia-Da","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Irvine, CA 92697;"}]},{"given":"Taneli","family":"Raivio","sequence":"additional","affiliation":[{"name":"*Reproductive Endocrine Unit, Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, MA 02114;"}]},{"given":"Lindsay W.","family":"Cole","sequence":"additional","affiliation":[{"name":"*Reproductive Endocrine Unit, Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, MA 02114;"}]},{"given":"Lacey","family":"Plummer","sequence":"additional","affiliation":[{"name":"*Reproductive Endocrine Unit, Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, MA 02114;"}]},{"given":"Elka E.","family":"Jacobson-Dickman","sequence":"additional","affiliation":[{"name":"*Reproductive Endocrine Unit, Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, MA 02114;"}]},{"given":"Pamela L.","family":"Mellon","sequence":"additional","affiliation":[{"name":"Departments of Reproductive Medicine and Neurosciences, University of California at San Diego, La Jolla, CA 92093"}]},{"given":"Qun-Yong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Irvine, CA 92697;"}]},{"suffix":"Jr.","given":"William F.","family":"Crowley","sequence":"additional","affiliation":[{"name":"*Reproductive Endocrine Unit, Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, MA 02114;"}]}],"member":"341","published-online":{"date-parts":[[2007,10,30]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"203","volume":"158","author":"Kallmann FJ","year":"1944","unstructured":"FJ Kallmann, WA Schoenfeld Am J Mental Defic 158, 203\u2013236 (1944).","journal-title":"Am J Mental 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