DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland

Autor(es)

Kizys, Marina M. L. ^[1] ; Louzada, Ruy A. ^{[2, 3, 4, 5]} ; Mitne-Neto, Miguel ^{[6, 7]} ; Jara, Jessica R. ; Furuzawa, Gilberto K. ^[1] ; de Carvalho, Denise P. ; Dias-da-Silva, Magnus R. ^[1] ; Nesi-Franca, Suzana ^[8] ; Dupuy, Corinne ^{[2, 3, 4]} ; Maciel, Rui M. B. ^{[6, 1]}

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Med, Lab Mol & Translat Endocrinol, BR-04039032 Sao Paulo - Brazil

^[2] CNRS, UMR 8200, F-94800 Villejuif - France

^[3] Inst Gustave Roussy, F-94800 Villejuif - France

^[4] Univ Paris Saclay, F-91405 Orsay - France

^[5] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Endocrine Physiol Doris Rosenthal, BR-21941902 Rio De Janeiro - Brazil

^[6] Fleury Grp, BR-04344070 Sao Paulo - Brazil

^[7] Univ Sao Paulo, Biosci Inst, Human Genome & Stem Cell Res Ctr, BR-05508900 Sao Paulo - Brazil

^[8] Univ Fed Parana, Dept Pediat, BR-80060240 Curitiba, Parana - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 102, n. 11, p. 4060-4071, NOV 1 2017.
• Citações Web of Science: 15

Resumo

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. (AU)

• Processo FAPESP: 14/15948-2 - Hipotiroidismo congênito: validação funcional in vivo do novo gene-candidato CCDC para o desenvolvimento da hemiagenesia tiroidiana
• Beneficiário: Marina Malta Letro Kizys Polisel
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 12/00079-3 - Disgenesias tiroidianas: rastreamento e estudo funcional de mutações dos genes candidatos NKX2.5, HAND2, ISL1, TBX1, HOXA3/HOXB3/HOXD3 e EYA1 numa coorte de 601 pacientes com hipotiroidismo congênito
• Beneficiário: Rui Monteiro de Barros Maciel
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/01628-0 - Disgenesias tiroidianas: análise molecular e estudo funcional de mutações em genes candidatos a partir do sequenciamento de última geração numa coorte de 268 casos
• Beneficiário: Marina Malta Letro Kizys Polisel
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto