POU6F2 mutation in humans with pubertal failure alters GnRH transcript expression

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dc.authoridKotan, Leman Damla/0000-0001-6176-8986
dc.authoridTURAN, IHSAN/0000-0002-5654-247X
dc.authoridFarmer, Stephen/0000-0002-4289-1257
dc.contributor.authorCho, Hyun-Ju
dc.contributor.authorGurbuz, Fatih
dc.contributor.authorStamou, Maria
dc.contributor.authorKotan, Leman Damla
dc.contributor.authorFarmer, Stephen Matthew
dc.contributor.authorCan, Sule
dc.contributor.authorTompkins, Miranda Faith
dc.date.accessioned2024-09-18T20:28:06Z
dc.date.available2024-09-18T20:28:06Z
dc.date.issued2023
dc.departmentHatay Mustafa Kemal Üniversitesien_US
dc.description.abstractIdiopathic hypogonadotropic hypogonadism (IHH) is characterized by the absence of pubertal development and subsequent impaired fertility often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2 in 15 patients. POU6F2 encodes two distinct isoforms. In the adult mouse, expression of both isoform1 and isoform2 was detected in the brain, pituitary, and gonads. However, only isoform1 was detected in mouse primary GnRH cells and three immortalized GnRH cell lines, two mouse and one human. To date, the function of isoform2 has been verified as a transcription factor, while the function of isoform1 has been unknown. In the present report, bioinformatics and cell assays on a human-derived GnRH cell line reveal a novel function for isoform1, demonstrating it can act as a transcriptional regulator, decreasing GNRH1 expression. In addition, the impact of the two most prevalent POU6F2 variants, identified in five IHH patients, that were located at/or close to the DNA-binding domain was examined. Notably, one of these mutations prevented the repression of GnRH transcripts by isoform1. Normally, GnRH transcription increases as GnRH cells mature as they near migrate into the brain. Augmentation earlier during development can disrupt normal GnRH cell migration, consistent with some POU6F2 variants contributing to the IHH pathogenesis.en_US
dc.description.sponsorshipUniversity of Mississippi Medical Centeren_US
dc.description.sponsorshipThis study was supported by University of Mississippi Medical Center, (grant DN00305, AT), Cukurova University (scientific research project number 11364, AT), National Institutes of Health, National Institute of Neurological Disorders and Stroke (ZIANS-002824-30-32, SW), Eunice K. Shriver National Institute for Child Health and Human Development (P50HD104224-01, RB and SS; R37 HD043341-19, R01 FD005712-04, SS).en_US
dc.identifier.doi10.3389/fendo.2023.1203542
dc.identifier.issn1664-2392
dc.identifier.pmid37600690en_US
dc.identifier.scopus2-s2.0-85168261520en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.urihttps://doi.org/10.3389/fendo.2023.1203542
dc.identifier.urihttps://hdl.handle.net/20.500.12483/10732
dc.identifier.volume14en_US
dc.identifier.wosWOS:001048852600001en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherFrontiers Media Saen_US
dc.relation.ispartofFrontiers in Endocrinologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectidiopathic hypogonadotropic hypogonadismen_US
dc.subjectGnRHen_US
dc.subjectPOU6f2 isoform1en_US
dc.subjecttranscriptionen_US
dc.subjectpubertyen_US
dc.titlePOU6F2 mutation in humans with pubertal failure alters GnRH transcript expressionen_US
dc.typeArticleen_US

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