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Fibroblast growth factor receptor 1 (\n                    <jats:italic>FGFR1<\/jats:italic>\n                    ) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH\n                    <jats:italic>FGFR1<\/jats:italic>\n                    mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with \u03b2\u2010Klotho (KLB), the obligate co\u2010receptor for FGF21. We thus hypothesized that the metabolic FGF21\/KLB\/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss\u2010of\u2010function\n                    <jats:italic>KLB<\/jats:italic>\n                    mutations in 13 patients (4%). Most patients with\n                    <jats:italic>KLB<\/jats:italic>\n                    mutations (9\/13) exhibited metabolic defects. In mice, lack of\n                    <jats:italic>Klb<\/jats:italic>\n                    led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21\/KLB\/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201607376","type":"journal-article","created":{"date-parts":[[2017,7,28]],"date-time":"2017-07-28T20:10:33Z","timestamp":1501272633000},"page":"1379-1397","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["KLB, encoding \u03b2\u2010Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism"],"prefix":"10.1038","volume":"9","author":[{"given":"Cheng","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Messina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Somm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hichem","family":"Miraoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarja","family":"Kinnunen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"James","family":"Acierno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas J","family":"Niederl\u00e4nder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Bouilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A","family":"Dwyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yisrael","family":"Sidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Cassatella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerasimos P","family":"Sykiotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Quinton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"De Geyter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Dirlewanger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Schwitzgebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor R","family":"Cole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A","family":"Toogood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy MW","family":"Kirk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lacey","family":"Plummer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-8676","authenticated-orcid":false,"given":"Urs","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"William F","family":"Crowley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moosa","family":"Mohammadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Tena\u2010Sempere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Prevot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0971-3237","authenticated-orcid":false,"given":"Nelly","family":"Pitteloud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,28]]},"reference":[{"key":"BFEMMM201607376_CR1","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. 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