Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorMACEDO, Delanie B.
dc.contributor.authorFRANCA, Monica M.
dc.contributor.authorMONTENEGRO, Luciana R.
dc.contributor.authorCUNHA-SILVA, Marina
dc.contributor.authorBESSA, Danielle S.
dc.contributor.authorABREU, Ana Paula
dc.contributor.authorKAISER, Ursula B.
dc.contributor.authorMENDONCA, Berenice B.
dc.contributor.authorJORGE, Alexander A. L.
dc.contributor.authorBRITO, Vinicius N.
dc.contributor.authorLATRONICO, Ana Claudia
dc.date.accessioned2018-11-21T17:00:07Z
dc.date.available2018-11-21T17:00:07Z
dc.date.issued2018
dc.description.abstractContext: Loss-of-function mutations in the coding region of MKRN3, a maternally imprinted gene at chromosome 15q11.2, are a common cause of familial central precocious puberty (CPP). Whether MKRN3 alterations in regulatory regions can cause CPP has not been explored to date. We aimed to investigate potential pathogenic variants in the promoter region of MKRN3 in patients with idiopathic CPP. Patients/Methods: A cohort of 110 patients with idiopathic CPP was studied. Family history of precocious sexual development was present in 25%. Mutations in the coding region of MKRN3 were excluded in all patients. Genomic DNA was extracted from peripheral blood leukocytes, and 1,100 nucleotides (nt) of the 5'-regulatory region of MKRN3 were amplified and sequenced. Luciferase assays were performed in GT1-7 cells transiently transfected with plasmids containing mutated and wild-type MKRN3 promoter. Results: We identified a rare heterozygous 4-nt deletion (c.-150_-147delTCAG; -38 to -41 nt upstream to the transcription start site) in the proximal promoter region of MKRN3 in a girl with CPP. In silico analysis predicted that this deletion would lead to the loss of a binding site for a downstream responsive element antagonist modulator (DREAM), a potential transcription factor for MKRN3 and GNRH1 expression. Luciferase assays demonstrated a significant reduction of MKRN3 promoter activity in transfected cells with a c.-150_-147delTCAG construct plasmid in both homozygous and heterozygous states when compared with cells transfected with the corresponding wild-type MKRN3 promoter region. Conclusion: A rare genetic alteration in the regulatory region of MKRN3 causes CPP. (c) 2018 S. Karger AG, Basel
dc.description.indexMEDLINE
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico [302849/2015-7, 303002/2016-6]
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo [13/03236-5, 2013/06391-1, 2014/50137-5]
dc.description.sponsorshipNational Institutes of Health [R01 HD082314]
dc.identifier.citationNEUROENDOCRINOLOGY, v.107, n.2, p.127-132, 2018
dc.identifier.doi10.1159/000490059
dc.identifier.eissn1423-0194
dc.identifier.issn0028-3835
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/29365
dc.language.isoeng
dc.publisherKARGER
dc.relation.ispartofNeuroendocrinology
dc.rightsrestrictedAccess
dc.rights.holderCopyright KARGER
dc.subjectCentral precocious puberty
dc.subjectMKRN3 promoter region
dc.subjectGenetic alteration
dc.subjectRegulatory region
dc.subject.otherimprinted gene mkrn3
dc.subject.otherdream protein
dc.subject.otherprader-willi
dc.subject.otherexpression
dc.subject.othermutations
dc.subject.otherring
dc.subject.othertranscription
dc.subject.wosEndocrinology & Metabolism
dc.subject.wosNeurosciences
dc.titleCentral Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryisous
hcfmusp.author.externalABREU, Ana Paula:Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA; Harvard Med Sch, Boston, MA USA
hcfmusp.author.externalKAISER, Ursula B.:Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA; Harvard Med Sch, Boston, MA USA
hcfmusp.citation.scopus23
hcfmusp.contributor.author-fmusphcFRANCISCA DELANIE BULCAO DE MACEDO
hcfmusp.contributor.author-fmusphcMONICA MALHEIROS FRANCA
hcfmusp.contributor.author-fmusphcLUCIANA RIBEIRO MONTENEGRO
hcfmusp.contributor.author-fmusphcMARINA CUNHA SILVA PAZOLINI
hcfmusp.contributor.author-fmusphcDANIELLE DE SOUZA BESSA
hcfmusp.contributor.author-fmusphcBERENICE BILHARINHO DE MENDONCA
hcfmusp.contributor.author-fmusphcALEXANDER AUGUSTO DE LIMA JORGE
hcfmusp.contributor.author-fmusphcVINICIUS NAHIME DE BRITO
hcfmusp.contributor.author-fmusphcANA CLAUDIA LATRONICO XAVIER
hcfmusp.description.beginpage127
hcfmusp.description.endpage132
hcfmusp.description.issue2
hcfmusp.description.volume107
hcfmusp.origemWOS
hcfmusp.origem.pubmed29763903
hcfmusp.origem.scopus2-s2.0-85053331005
hcfmusp.origem.wosWOS:000444751900003
hcfmusp.publisher.cityBASEL
hcfmusp.publisher.countrySWITZERLAND
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hcfmusp.scopus.lastupdate2024-05-10
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