{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T04:09:37Z","timestamp":1791691777473,"version":"4.3.4"},"reference-count":19,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,10,1]]},"abstract":"<jats:p>Context: Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice.<\/jats:p>\n               <jats:p>Objective: To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities.<\/jats:p>\n               <jats:p>Design: We studied 107 Brazilian patients with HH (63 with Kallmann syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing.<\/jats:p>\n               <jats:p>Results: In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann syndrome harbored the homozygous p.G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p.I55fsX56 mutation. In PROKR2, four distinct mutations (p.R80C, p.Y140X, p.L173R, and p.R268C) were identified in five patients with Kallmann syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p.R80C, p.L173R, and p.R268C missense mutations were identified in the heterozygous state in the HH patients and in their asymptomatic first-degree relatives. In addition, no mutations of FGFR1, KAL1, GnRHR, KiSS-1, or GPR54 were identified in these patients. Notably, the new nonsense mutation (p.Y140X) was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous for this severe defect.<\/jats:p>\n               <jats:p>Conclusion: We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.<\/jats:p>","DOI":"10.1210\/jc.2008-0958","type":"journal-article","created":{"date-parts":[[2008,8,6]],"date-time":"2008-08-06T03:48:58Z","timestamp":1217994538000},"page":"4113-4118","source":"Crossref","is-referenced-by-count":100,"title":["Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome"],"prefix":"10.1210","volume":"93","author":[{"given":"Ana Paula","family":"Abreu","sequence":"first","affiliation":[{"name":"Developmental Endocrinology Unit (A.P.A., E.B.T., E.M.F.C., B.B.M., A.C.L.), Laboratory of Hormone and Molecular Genetic Laboratory of Medical Investigation-42, Clinical Hospital, Medical School, Sao Paulo University, 05403-900 Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ericka Barbosa","family":"Trarbach","sequence":"additional","affiliation":[{"name":"Developmental Endocrinology Unit (A.P.A., E.B.T., E.M.F.C., B.B.M., A.C.L.), Laboratory of Hormone and Molecular Genetic Laboratory of Medical Investigation-42, Clinical Hospital, Medical School, Sao Paulo University, 05403-900 Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"de Castro","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (M.d.C., B.V.), Clinical Hospital, Medical School of Ribeirao Preto University of Sao Paulo, 14049-900 Ribeirao Preto, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine Maria","family":"Frade Costa","sequence":"additional","affiliation":[{"name":"Developmental Endocrinology Unit (A.P.A., E.B.T., E.M.F.C., B.B.M., A.C.L.), Laboratory of Hormone and Molecular Genetic Laboratory of Medical Investigation-42, Clinical Hospital, Medical School, Sao Paulo University, 05403-900 Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Versiani","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (M.d.C., B.V.), Clinical Hospital, Medical School of Ribeirao Preto University of Sao Paulo, 14049-900 Ribeirao Preto, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Tereza","family":"Matias Baptista","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (M.T.M.B., H.M.G.), Clinical Hospital, State University of Campinas, Campinas, 13083-970 Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heraldo Mendes","family":"Garmes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (M.T.M.B., H.M.G.), Clinical Hospital, State University of Campinas, Campinas, 13083-970 Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berenice Bilharinho","family":"Mendonca","sequence":"additional","affiliation":[{"name":"Developmental Endocrinology Unit (A.P.A., E.B.T., E.M.F.C., B.B.M., A.C.L.), Laboratory of Hormone and Molecular Genetic Laboratory of Medical Investigation-42, Clinical Hospital, Medical School, Sao Paulo University, 05403-900 Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Claudia","family":"Latronico","sequence":"additional","affiliation":[{"name":"Developmental Endocrinology Unit (A.P.A., E.B.T., E.M.F.C., B.B.M., A.C.L.), Laboratory of Hormone and Molecular Genetic Laboratory of Medical Investigation-42, Clinical Hospital, Medical School, Sao Paulo University, 05403-900 Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071613484223800_R1","first-page":"521","article-title":"Gonadotropin-releasing 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(Oxf)"},{"key":"2020071613484223800_R10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1590\/S1415-47572004000300006","article-title":"Similar interstitial deletions of the KAL-1 gene in two Brazilian families with X-linked Kallmann syndrome.","volume":"27","author":"Trarbach","year":"2004","journal-title":"Genet Mol Biol"},{"key":"2020071613484223800_R11","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1677\/joe.1.06103","article-title":"Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients.","volume":"187","author":"Trarbach","year":"2005","journal-title":"J Endocrinol"},{"key":"2020071613484223800_R12","first-page":"2680","article-title":"Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction.","volume":"86","author":"Costa","year":"2001","journal-title":"J Clin Endocrinol 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The alcohol sniff test.","volume":"123","author":"Davidson","year":"1997","journal-title":"Arch Otolaryngol Head Neck Surg"},{"key":"2020071613484223800_R14","first-page":"3539","article-title":"Diagnostic value of fluorometric assays in the evaluation of precocious puberty.","volume":"84","author":"Brito","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613484223800_R15","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1126\/science.1112103","article-title":"Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling.","volume":"308","author":"Ng","year":"2005","journal-title":"Science"},{"key":"2020071613484223800_R16","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1172\/JCI29884","article-title":"Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.","volume":"117","author":"Pitteloud","year":"2007","journal-title":"J Clin Invest"},{"key":"2020071613484223800_R17","doi-asserted-by":"crossref","first-page":"4006","DOI":"10.1210\/jc.2005-2793","article-title":"Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.","volume":"91","author":"Trarbach","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613484223800_R18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s11154-007-9027-3","article-title":"Human genetics of GPR54.","volume":"8","author":"Cerrato","year":"2007","journal-title":"Rev Endocr Metab Disord"},{"key":"2020071613484223800_R19","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/sj.bjp.0705686","article-title":"Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats.","volume":"142","author":"Negri","year":"2004","journal-title":"Br J Pharmacol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/93\/10\/4113\/9057210\/jcem4113.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/93\/10\/4113\/9057210\/jcem4113.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:41:55Z","timestamp":1594946515000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/93\/10\/4113\/2627409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,10,1]]},"references-count":19,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2008,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2008-0958","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,10,1]]}}}