DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland

DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland

Author Kizys, Marina M. L. Autor UNIFESP Google Scholar
Louzada, Ruy A. Google Scholar
Mitne-Neto, Miguel Google Scholar
Jara, Jessica R. Google Scholar
Furuzawa, Gilberto K. Autor UNIFESP Google Scholar
de Carvalho, Denise P. Google Scholar
Dias-da-Silva, Magnus R. Autor UNIFESP Google Scholar
Nesi-Franca, Suzana Google Scholar
Dupuy, Corinne Google Scholar
Maciel, Rui M. B. Autor UNIFESP Google Scholar
Abstract Context: 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.
xmlui.dri2xhtml.METS-1.0.item-coverage Cary
Language English
Sponsor Sao Paulo Research Foundation (FAPESP)
Fleury Group
Grant number FAPESP: 2012/00079-3
FAPESP: 2012/01628-0
FAPESP: 2014/15948-2
Fleury Group: P&D NP-82: FINEP 0914005500
Date 2017
Published in Journal Of Clinical Endocrinology & Metabolism. Cary, v. 102, n. 11, p. 4060-4071, 2017.
ISSN 0021-972X (Sherpa/Romeo, impact factor)
Publisher Oxford Univ Press Inc
Extent 4060-4071
Origin http://dx.doi.org/10.1210/jc.2017-00832
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000414558500020
URI https://repositorio.unifesp.br/handle/11600/58274

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