{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:26:21Z","timestamp":1791300381331,"version":"4.1.0"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"1","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,7]]},"abstract":"<jats:sec><jats:title>Context<\/jats:title><jats:p>Loss-of-function mutations of the kisspeptin-1 receptor gene, <jats:italic>KISS1R<\/jats:italic>, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate <jats:italic>KISS1R<\/jats:italic> defects in patients with absent or delayed puberty.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients<\/jats:title><jats:p>We investigated <jats:italic>KISS1R<\/jats:italic> gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The entire coding region of <jats:italic>KISS1R<\/jats:italic> was amplified by PCR followed by automatic sequencing. In addition, screening for <jats:italic>KISS1R<\/jats:italic> exonic deletions was performed by multiplex ligation-dependent probe amplification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>One novel homozygous <jats:italic>KISS1R<\/jats:italic> mutation was identified in two siblings with nIHH. This variant was an insertion\/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position \u22122 to \u22124, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3\u2032 splice acceptor site of intron 2 of <jats:italic>KISS1R<\/jats:italic>. The brothers who carried this <jats:italic>KISS1R<\/jats:italic> mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous <jats:italic>KISS1R<\/jats:italic> variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, <jats:italic>in vitro<\/jats:italic> studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Loss-of-function mutations of <jats:italic>KISS1R<\/jats:italic> represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel <jats:italic>KISS1R<\/jats:italic> homozygous splice acceptor site mutation in the familial form of nIHH.<\/jats:p><\/jats:sec>","DOI":"10.1530\/eje-10-0012","type":"journal-article","created":{"date-parts":[[2010,4,7]],"date-time":"2010-04-07T05:41:02Z","timestamp":1270618862000},"page":"29-34","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":50,"title":["A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism"],"prefix":"10.1093","volume":"163","author":[{"given":"M G","family":"Teles","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E B","family":"Trarbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S D","family":"Noel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Guerra-Junior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Jorge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Beneduzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S D","family":"Bianco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M T","family":"Baptista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E M","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"De Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B B","family":"Mendon\u00e7a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U B","family":"Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A C","family":"Latronico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"issue":"20","key":"1_8781866","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1056\/NEJM198211113072003","volume":"307","author":"Hoffman","year":"1982","journal-title":"New England Journal of Medicine","ISSN":"https:\/\/id.crossref.org\/issn\/0028-4793","issn-type":"print"},{"issue":"4","key":"2_6301777","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/S0889-8529(05)70039-6","volume":"27","author":"Hayes","year":"1998","journal-title":"Endocrinology and metabolism clinics of North America","ISSN":"https:\/\/id.crossref.org\/issn\/0889-8529","issn-type":"print"},{"issue":"17","key":"3_17870440","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1056\/NEJMoa035322","volume":"349","author":"Seminara","year":"2003","journal-title":"New England Journal of Medicine","ISSN":"https:\/\/id.crossref.org\/issn\/0028-4793","issn-type":"print"},{"issue":"19","key":"4_19683289","doi-asserted-by":"publisher","first-page":"10972","DOI":"10.1073\/pnas.1834399100","volume":"100","year":"2003","journal-title":"PNAS","ISSN":"https:\/\/id.crossref.org\/issn\/0027-8424","issn-type":"print"},{"issue":"3","key":"5_18745074","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1210\/jc.2004-1418","volume":"90","year":"2005","journal-title":"Journal of Clinical Endocrinology &amp; 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