{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:31:12Z","timestamp":1791268272189,"version":"4.1.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"28","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,7,14]]},"abstract":"<jats:p>\n                    Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene,\n                    <jats:italic>GNRH1<\/jats:italic>\n                    itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in\n                    <jats:italic>GNRH1<\/jats:italic>\n                    . In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in\n                    <jats:italic>GNRH1<\/jats:italic>\n                    as a genetic cause of nIHH.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0903449106","type":"journal-article","created":{"date-parts":[[2009,6,30]],"date-time":"2009-06-30T22:38:55Z","timestamp":1246401535000},"page":"11703-11708","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":161,"title":["<i>GNRH1<\/i>\n                    mutations in patients with idiopathic hypogonadotropic hypogonadism"],"prefix":"10.1073","volume":"106","author":[{"given":"Yee-Ming","family":"Chan","sequence":"first","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"},{"name":"Department of Medicine, Division of Endocrinology, Children's Hospital Boston, 333 Longwood Avenue, 6th Floor, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelaide","family":"de Guillebon","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarosaria","family":"Lang-Muritano","sequence":"additional","affiliation":[{"name":"Pediatric Endocrine Unit, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey","family":"Plummer","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felecia","family":"Cerrato","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Tsiaras","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariana","family":"Gaspert","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne B.","family":"Lavoie","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, 1058 St-Denis, Montreal, QC, Canada H2X 3J4;"},{"name":"PROCREA Cliniques, Montreal, QC, Canada H4P 2R2;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Hui","family":"Wu","sequence":"additional","affiliation":[{"name":"2500 Nesconset Highway, #12C, Stony Brook, NY 11790; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"William F.","family":"Crowley","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"Amory","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine, University of Washington Medical Center, Campus Box 356429, 1959 NE Pacific Street, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Pitteloud","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie B.","family":"Seminara","sequence":"additional","affiliation":[{"name":"Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BHX 5, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,7,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-3565-9"},{"key":"e_1_3_4_2_2","first-page":"127","article-title":"Experimental hypophysectomy","volume":"21","author":"Crowe S","year":"1910","unstructured":"S Crowe, H Cushing, J Homans, Experimental hypophysectomy. 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