{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T19:59:30Z","timestamp":1775159970216,"version":"3.50.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["1R01HD084542"],"award-info":[{"award-number":["1R01HD084542"]}]},{"name":"National Institute of Health","award":["8P51OD011092"],"award-info":[{"award-number":["8P51OD011092"]}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L002671\/1"],"award-info":[{"award-number":["BB\/L002671\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000833","name":"Rosetrees Trust","doi-asserted-by":"publisher","award":["M222-F1"],"award-info":[{"award-number":["M222-F1"]}],"id":[{"id":"10.13039\/501100000833","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["105519\/Z\/14\/Z"],"award-info":[{"award-number":["105519\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["102745"],"award-info":[{"award-number":["102745"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.<\/jats:p>","DOI":"10.1093\/hmg\/ddy451","type":"journal-article","created":{"date-parts":[[2019,1,2]],"date-time":"2019-01-02T15:09:07Z","timestamp":1546441747000},"page":"1357-1368","source":"Crossref","is-referenced-by-count":33,"title":["EAP1 regulation of GnRH promoter activity is important for human pubertal timing"],"prefix":"10.1093","volume":"28","author":[{"given":"Alessandra","family":"Mancini","sequence":"first","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sasha R","family":"Howard","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia P","family":"Cabrera","sequence":"additional","affiliation":[{"name":"Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R","family":"Barnes","sequence":"additional","affiliation":[{"name":"Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"David","sequence":"additional","affiliation":[{"name":"Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karoliina","family":"Wehkalampi","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Heger","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Children\u2019s Hospital Auf der Bult, Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Lomniczi","sequence":"additional","affiliation":[{"name":"Oregon National Primate Research Center\/Oregon Health and Science University, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Guasti","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio R","family":"Ojeda","sequence":"additional","affiliation":[{"name":"Oregon National Primate Research Center\/Oregon Health and Science University, Portland, OR, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo","family":"Dunkel","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,1,4]]},"reference":[{"key":"2019121022394232200_ref1","first-page":"739","article-title":"Common genetic influences on BMI and age at menarche","volume":"67","author":"Kaprio","year":"1995","journal-title":"Hum. 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