DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland

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dc.citation.issue11
dc.citation.volume102
dc.contributor.authorKizys, Marina M. L. [UNIFESP]
dc.contributor.authorLouzada, Ruy A.
dc.contributor.authorMitne-Neto, Miguel
dc.contributor.authorJara, Jessica R.
dc.contributor.authorFuruzawa, Gilberto K. [UNIFESP]
dc.contributor.authorde Carvalho, Denise P.
dc.contributor.authorDias-da-Silva, Magnus R. [UNIFESP]
dc.contributor.authorNesi-Franca, Suzana
dc.contributor.authorDupuy, Corinne
dc.contributor.authorMaciel, Rui M. B. [UNIFESP]
dc.coverageCary
dc.date.accessioned2020-09-01T13:21:27Z
dc.date.available2020-09-01T13:21:27Z
dc.date.issued2017
dc.description.abstractContext: Thyroid dysgenesis (TD) is the leading cause of congenital hypothyroidism (CH). The etiology of TD remains unknown in; 90% of cases, the most common form being thyroid ectopia (TE) (48% to 61%). Objective: To search for candidate genes in hypothyroid children with TE. Design, Setting, and Participants: We followed a cohort of 268 children with TD and performed whole-exome sequencing (WES) in three children with CH with TE (CHTE) and compared them with 18 thyroid-healthy controls. We then screened an additional 41 children with CHTE by Sanger sequencing and correlated the WES and Sanger molecular findings with in vitro functional analysis. Main Outcome Measures: Genotyping, mutation prediction analysis, and in vitro functional analysis. Results: Weidentified seven variants in the DUOX2 gene, namely G201E, L264CfsX57, P609S, M650T, E810X, M822V, and E1017G, and eight known variations. All children carrying DUOX2 variations had high thyroid-stimulating hormone levels at neonatal diagnosis. All mutations were localized in the N-terminal segment, and three of them led to effects on cell surface targeting and reactive oxygen species generation. The DUOX2 mutants also altered the interaction with the maturation factor DUOXA2 and the formation of a stable DUOX2/DUOXA2 complex at the cell surface, thereby impairing functional enzymatic activity. Weobserved no mutations in the classic genes related to TD or in the DUOX1 gene. Conclusion: Our findings suggest that, in addition to thyroid hormonogenesis, the DUOX2 N-terminal domainmay play a role in thyroid development.en
dc.description.affiliationUniv Fed Sao Paulo, Dept Med, Lab Mol & Translat Endocrinol, BR-04039032 Sao Paulo, Brazil
dc.description.affiliationCNRS, UMR 8200, F-94800 Villejuif, France
dc.description.affiliationInst Gustave Roussy, F-94800 Villejuif, France
dc.description.affiliationUniv Paris Saclay, F-91405 Orsay, France
dc.description.affiliationUniv Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Endocrine Physiol Doris Rosenthal, BR-21941902 Rio De Janeiro, Brazil
dc.description.affiliationFleury Grp, BR-04344070 Sao Paulo, Brazil
dc.description.affiliationUniv Sao Paulo, Biosci Inst, Human Genome & Stem Cell Res Ctr, BR-05508900 Sao Paulo, Brazil
dc.description.affiliationUniv Fed Parana, Dept Pediat, BR-80060240 Curitiba, Parana, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Med, Lab Mol & Translat Endocrinol, BR-04039032 Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipSao Paulo Research Foundation (FAPESP)
dc.description.sponsorshipFleury Group
dc.description.sponsorshipIDFAPESP: 2012/00079-3
dc.description.sponsorshipIDFAPESP: 2012/01628-0
dc.description.sponsorshipIDFAPESP: 2014/15948-2
dc.description.sponsorshipIDFleury Group: P&D NP-82: FINEP 0914005500
dc.format.extent4060-4071
dc.identifierhttp://dx.doi.org/10.1210/jc.2017-00832
dc.identifier.citationJournal Of Clinical Endocrinology & Metabolism. Cary, v. 102, n. 11, p. 4060-4071, 2017.
dc.identifier.doi10.1210/jc.2017-00832
dc.identifier.issn0021-972X
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/58274
dc.identifier.wosWOS:000414558500020
dc.language.isoeng
dc.publisherOxford Univ Press Inc
dc.relation.ispartofJournal Of Clinical Endocrinology & Metabolism
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleDUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Glanden
dc.typeinfo:eu-repo/semantics/article
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