dc.contributor.author | Mancini, A | |
dc.contributor.author | Howard, SR | |
dc.contributor.author | Cabrera, CP | |
dc.contributor.author | Barnes, MR | |
dc.contributor.author | David, A | |
dc.contributor.author | Wehkalampi, K | |
dc.contributor.author | Heger, S | |
dc.contributor.author | Lomniczi, A | |
dc.contributor.author | Guasti, L | |
dc.contributor.author | Ojeda, SR | |
dc.contributor.author | Dunkel, L | |
dc.date.accessioned | 2019-01-31T15:38:26Z | |
dc.date.available | 2018-12-24 | |
dc.date.available | 2019-01-31T15:38:26Z | |
dc.date.issued | 2019-01-04 | |
dc.identifier.citation | Mancini, A., et al. (2019). "EAP1 regulation of GnRH promoter activity is important for human pubertal timing.. Human Molecular Genetics, ddy451, https://doi.org/10.1093/hmg/ddy451 | en_US |
dc.identifier.issn | 0964-6906 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/55065 | |
dc.description | This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Mancini, A., et al. (2019). "EAP1 regulation of GnRH promoter activity is important for human pubertal timing." is available online at: https://doi.org/10.1093/hmg/ddy451 | en_US |
dc.description.abstract | 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 analysed 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 (ChIP). 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 sub-cellular mis-location 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. | en_US |
dc.description.sponsorship | National Institute for Health Research (to S.R.H.); Wellcome Trust (102745 to S.R.H. and 105519/Z/14/Z to A.D.); Rosetrees Trust (M222-F1 to S.R.H.); Biotechnology and Biological Sciences Research Council (BB/L002671/1 to L.G.); National Institute of Health (1R01HD084542 and 8P51OD011092 to S.R.O. | en_US |
dc.language | eng | |
dc.language.iso | en | en_US |
dc.publisher | Oxford University Press | en_US |
dc.relation.ispartof | Hum Mol Genet | |
dc.rights | Creative Commons Attribution | |
dc.subject | transcription, genetic western blotting mutation gonadotropin-releasing hormone chromatin fluorescent antibody technique hypothalamus mice puberty proband whole exome sequencing | en_US |
dc.subject | transcription | en_US |
dc.subject | transcription | en_US |
dc.subject | genetic | en_US |
dc.subject | western blotting | en_US |
dc.subject | mutation | en_US |
dc.subject | gonadotropin-releasing hormone | en_US |
dc.subject | chromatin | en_US |
dc.subject | fluorescent antibody technique | en_US |
dc.subject | hypothalamus | en_US |
dc.subject | proband | en_US |
dc.subject | whole exome sequencing | en_US |
dc.title | EAP1 regulation of GnRH promoter activity is important for human pubertal timing. | en_US |
dc.type | Article | en_US |
dc.rights.holder | The Author(s) 2019 | |
dc.identifier.doi | 10.1093/hmg/ddy451 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/30608578 | en_US |
pubs.notes | No embargo | en_US |
pubs.publication-status | Published online | en_US |
dcterms.dateAccepted | 2018-12-24 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
qmul.funder | Novel genes underlying the timing of puberty::Wellcome Trust | en_US |
qmul.funder | Novel genes underlying the timing of puberty::Wellcome Trust | en_US |
qmul.funder | Novel genes underlying the timing of puberty::Wellcome Trust | en_US |
qmul.funder | Novel genes underlying the timing of puberty::Wellcome Trust | en_US |
qmul.funder | Novel genes underlying the timing of puberty::Wellcome Trust | en_US |