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DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland
- Source :
- Journal of Clinical Endocrinology and Metabolism, Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2017, 102 (11), pp.4060-4071. ⟨10.1210/jc.2017-00832⟩
- Publication Year :
- 2017
- Publisher :
- The Endocrine Society, 2017.
-
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 We identified 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. We observed 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 domain may play a role in thyroid development.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Candidate gene
Endocrinology, Diabetes and Metabolism
DNA Mutational Analysis
Clinical Biochemistry
Thyroid Gland
Context (language use)
medicine.disease_cause
Biochemistry
Thyroid dysgenesis
Cohort Studies
03 medical and health sciences
symbols.namesake
Endocrinology
Protein Domains
Internal medicine
Congenital Hypothyroidism
medicine
Humans
Genetic Predisposition to Disease
ComputingMilieux_MISCELLANEOUS
Genetic Association Studies
Congenital Hypothyroidism with Ectopic Thyroid
Sanger sequencing
Mutation
business.industry
Biochemistry (medical)
Thyroid
Infant, Newborn
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
medicine.disease
Dual Oxidases
3. Good health
Congenital hypothyroidism
HEK293 Cells
030104 developmental biology
medicine.anatomical_structure
Thyroid Dysgenesis
symbols
Female
business
Subjects
Details
- ISSN :
- 19457197 and 0021972X
- Volume :
- 102
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Endocrinology & Metabolism
- Accession number :
- edsair.doi.dedup.....c11f7bb8c0b073f7898f1f946dfd5141