Rare variants in the<i> MECP2</i> gene in girls with central precocious puberty: a translational cohort study

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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.authorCANTON, Ana P. M.
dc.contributor.authorTINANO, Flavia R.
dc.contributor.authorGUASTI, Leonardo
dc.contributor.authorMONTENEGRO, Luciana R.
dc.contributor.authorRYAN, Fiona
dc.contributor.authorSHEARS, Deborah
dc.contributor.authorMELO, Maria Edna de
dc.contributor.authorGOMES, Larissa G.
dc.contributor.authorPIANA, Mariana P.
dc.contributor.authorBRAUNER, Raja
dc.contributor.authorESPINO-AGUILAR, Rafael
dc.contributor.authorESCRIBANO-MUNOZ, Arancha
dc.contributor.authorPAGANONI, Alyssa
dc.contributor.authorREAD, Jordan E.
dc.contributor.authorKORBONITS, Marta
dc.contributor.authorSERAPHIM, Carlos E.
dc.contributor.authorCOSTA, Silvia S.
dc.contributor.authorKREPISCHI, Ana Cristina
dc.contributor.authorJORGE, Alexander A. L.
dc.contributor.authorDAVID, Alessia
dc.contributor.authorKAISINGER, Lena R.
dc.contributor.authorONG, Ken K.
dc.contributor.authorPERRY, John R. B.
dc.contributor.authorABREU, Ana Paula
dc.contributor.authorKAISER, Ursula B.
dc.contributor.authorARGENTE, Jesus
dc.contributor.authorMENDONCA, Berenice B.
dc.contributor.authorBRITO, Vinicius N.
dc.contributor.authorHOWARD, Sasha R.
dc.contributor.authorLATRONICO, Ana Claudia
dc.date.accessioned2023-10-30T14:24:27Z
dc.date.available2023-10-30T14:24:27Z
dc.date.issued2023
dc.description.abstractBackground Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. Methods In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. Findings Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3 & PRIME;UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. Interpretation We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process.eng
dc.description.indexMEDLINE
dc.description.indexPubMed
dc.description.indexWoS
dc.description.indexScopus
dc.identifier.citationLANCET DIABETES & ENDOCRINOLOGY, v.11, n.8, p.545-554, 2023
dc.identifier.doi10.1016/S2213-8587(23)00131-6
dc.identifier.eissn2213-8595
dc.identifier.issn2213-8587
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/55961
dc.language.isoeng
dc.publisherELSEVIER SCIENCE INCeng
dc.relation.ispartofLancet Diabetes & Endocrinology
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright ELSEVIER SCIENCE INCeng
dc.subject.otherrett-syndromeeng
dc.subject.otherx-chromosomeeng
dc.subject.othermecp2eng
dc.subject.othermutationseng
dc.subject.otherdiagnosiseng
dc.subject.otherfxyd1eng
dc.subject.wosEndocrinology & Metabolismeng
dc.titleRare variants in the<i> MECP2</i> gene in girls with central precocious puberty: a translational cohort studyeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryEspanha
hcfmusp.affiliation.countryInglaterra
hcfmusp.affiliation.countryFrança
hcfmusp.affiliation.countryisogb
hcfmusp.affiliation.countryisofr
hcfmusp.affiliation.countryisoes
hcfmusp.author.externalGUASTI, Leonardo:Queen Mary Univ London, William Harvey Res Inst, Ctr Endocrinol, Barts & London Sch Med & Dent, London, England
hcfmusp.author.externalRYAN, Fiona:Oxford Univ Hosp NHS Fdn Trust, Oxford Childrens Hosp, Oxford, England
hcfmusp.author.externalPIANA, Mariana P.:Oxford Univ Hosp NHS Fdn Trust, Oxford Ctr Genom Med, Oxford, England
hcfmusp.author.externalBRAUNER, Raja:Childrens State Hosp Vila Velha, Vila Velha, Brazil; Fdn Ophtalmol Adolphe Rothschild, Paris, France
hcfmusp.author.externalESPINO-AGUILAR, Rafael:Univ Paris, Paris, France; Univ Seville, Hosp Univ Virgen Valmes, Seville, Spain
hcfmusp.author.externalPAGANONI, Alyssa:Queen Mary Univ London, William Harvey Res Inst, Ctr Endocrinol, Barts & London Sch Med & Dent, London, England
hcfmusp.author.externalREAD, Jordan E.:Univ Sao Paulo, Genet Endocrinol Unit LIM 25, Sao Paulo, Brazil
hcfmusp.author.externalCOSTA, Silvia S.:Univ Sao Paulo, Clin Hosp, Sch Med, Discipline Endocrinol & Metab, Sao Paulo, Brazil; Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo, Brazil
hcfmusp.author.externalKREPISCHI, Ana Cristina:Univ Sao Paulo, Clin Hosp, Sch Med, Discipline Endocrinol & Metab, Sao Paulo, Brazil; Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo, Brazil
hcfmusp.author.externalONG, Ken K.:Virgen Arrixaca Univ Hosp, Dept Pediat, Endocrinol Unit, Murcia, Spain
hcfmusp.author.externalABREU, Ana Paula:Imperial Coll London, Ctr Integrat Syst Biol & Bioinformat, Dept Life Sci, London, England
hcfmusp.author.externalKAISER, Ursula B.:Imperial Coll London, Ctr Integrat Syst Biol & Bioinformat, Dept Life Sci, London, England
hcfmusp.citation.scopus8
hcfmusp.contributor.author-fmusphcANA PINHEIRO MACHADO CANTON
hcfmusp.contributor.author-fmusphcFLAVIA REZENDE TINANO
hcfmusp.contributor.author-fmusphcLUCIANA RIBEIRO MONTENEGRO
hcfmusp.contributor.author-fmusphcMARIA EDNA DE MELO
hcfmusp.contributor.author-fmusphcLARISSA GARCIA GOMES
hcfmusp.contributor.author-fmusphcCARLOS EDUARDO SERAPHIM
hcfmusp.contributor.author-fmusphcALEXANDER AUGUSTO DE LIMA JORGE
hcfmusp.contributor.author-fmusphcBERENICE BILHARINHO DE MENDONCA
hcfmusp.contributor.author-fmusphcVINICIUS NAHIME DE BRITO
hcfmusp.contributor.author-fmusphcANA CLAUDIA LATRONICO XAVIER
hcfmusp.description.beginpage545
hcfmusp.description.endpage554
hcfmusp.description.issue8
hcfmusp.description.volume11
hcfmusp.origemWOS
hcfmusp.origem.pubmed37385287
hcfmusp.origem.scopus2-s2.0-85165629504
hcfmusp.origem.wosWOS:001047258600001
hcfmusp.publisher.cityNEW YORKeng
hcfmusp.publisher.countryUSAeng
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