DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland

Author(s)

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]}

Affiliation

^[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

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 102, n. 11, p. 4060-4071, NOV 1 2017.
• Web of Science Citations: 15

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. (AU)

• FAPESP's process: 14/15948-2 - Congenital hypothyroidism: in vivo functional validation of the new candidate-gene CCDC for thyroid hemiagenesis
• Grantee: Marina Malta Letro Kizys Polisel
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 12/00079-3 - Thyroid dysgenesis: screening and functional analyses of mutations of the candidate-genes NKX2.5, HAND2, ISL1, TBX1, HOXA3/HOXB3/HOXD3 and EYA1 in a cohort of 601 patients with congenital hypothyroidism
• Grantee: Rui Monteiro de Barros Maciel
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/01628-0 - Thyroid dysgenesis: molecular analysis and functional studies of mutations in candidate genes discovered by next generation sequence in a cohort of 268 cases
• Grantee: Marina Malta Letro Kizys Polisel
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)