Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination

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dc.authorwosidLatronico, Ana Claudia/E-1198-2012
dc.contributor.authorMagnotto, John C.
dc.contributor.authorMancini, Alessandra
dc.contributor.authorBird, Keisha
dc.contributor.authorMontenegro, Luciana
dc.contributor.authorTutunculer, Filiz
dc.contributor.authorPereira, Sidney A.
dc.contributor.authorSimas, Vitoria
dc.date.accessioned2024-06-12T10:58:51Z
dc.date.available2024-06-12T10:58:51Z
dc.date.issued2023
dc.departmentTrakya Üniversitesien_US
dc.description.abstractContext Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. Objective This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. Methods Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5 ' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. Results Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. Conclusion MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.en_US
dc.description.sponsorshipNIH [R00 HD091381, R01 HD019938, R01 HD082314, R21 HD098684, K08 100595]; Brigham and Women's Hospital Women's Brain Initiativeen_US
dc.description.sponsorshipThis work was supported by NIH R00 HD091381 to A.P.A, and NIH R01 HD019938 to A.P.A and U.B.K; NIH R01 HD082314, R21 HD098684, and the Brigham and Women's Hospital Women's Brain Initiative to U.B.K, and NIH K08 100595 to S.A.R.en_US
dc.identifier.doi10.1210/clinem/dgad151
dc.identifier.endpage1656en_US
dc.identifier.issn0021-972X
dc.identifier.issn1945-7197
dc.identifier.issue7en_US
dc.identifier.pmid36916482en_US
dc.identifier.scopus2-s2.0-85163914075en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1646en_US
dc.identifier.urihttps://doi.org/10.1210/clinem/dgad151
dc.identifier.urihttps://hdl.handle.net/20.500.14551/20201
dc.identifier.volume108en_US
dc.identifier.wosWOS:000958921500001en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherEndocrine Socen_US
dc.relation.ispartofJournal Of Clinical Endocrinology & Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectCPPen_US
dc.subjectImprintingen_US
dc.subjectMKRN3en_US
dc.subjectDLK1en_US
dc.subjectImprinted Geneen_US
dc.subjectSerum Dlk1en_US
dc.subjectDiagnosisen_US
dc.subjectDeletionen_US
dc.subjectPatternen_US
dc.subjectProteinen_US
dc.subjectSwitchen_US
dc.subjectAgeen_US
dc.titleNovel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitinationen_US
dc.typeArticleen_US

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