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Identification and Functional Analysis of Novel Dual Oxidase 2 (DUOX2) Mutations in Children with Congenital or Subclinical Hypothyroidism

Authors :
Massimo Tonacchera
Lucia Montanelli
Caterina Di Cosmo
Angelo Molinaro
Patrizia Agretti
Paolo Vitti
Antonio Dimida
Claudia Ceccarelli
Aldo Pinchera
Giuseppina De Marco
Melissa De Servi
Brunella Bagattini
E. Ferrarini
Andrea Claudia Freitas Ferreira
Federica Brozzi
Source :
The Journal of Clinical Endocrinology & Metabolism. 96:E1335-E1339
Publication Year :
2011
Publisher :
The Endocrine Society, 2011.

Abstract

Congenital hypothyroidism (CH) associated with goiter or a gland of normal size has been linked to dual oxidase 2 (DUOX2) mutations in the presence of iodide organification defect.Thirty unrelated children with CH or subclinical hypothyroidism (SH) identified during infancy with a eutopic thyroid gland, coming from our Screening Centre for CH or referred from other regions of Italy, were studied with the perchlorate discharge test to identify organification defects. Eleven children with iodide organification defect were considered for the genetic analysis of TPO, DUOX2, and dual oxidase maturation factor 2 (DUOXA2) genes.Eight children with CH and three with SH and eutopic thyroid gland were included in the study. After discontinuation of therapy, a partial or complete organification defect was shown after ¹²³I scintigraphy and perchlorate test.TPO, DUOX2, and DUOXA2 genes were analyzed, and functional activity of DUOX2 variants was studied in HeLa cells.Sequencing of the DUOX2 gene revealed a deletion S965fsX994 in three children; two were euthyroid after 1 month of L-T₄ discontinuation but developed SH after 5 and 18 months, respectively, whereas the other child had SH. One child with SH showed H678R, R701Q, and P982A substitutions, and another child with SH showed only the P982A. One child with SH showed the Y1150C mutation, and another euthyroid child showed the A728T mutation. Functional studies confirmed that S965fsX994, Y1150C, and A728T mutations were responsible for the defect in H₂O₂ production, whereas H678R, R701Q, and P982A did not alter H₂O₂ production in vitro.Genetic analysis of the DUOX2 gene was performed in 11 children with organification defect. Two new mutations (Y1150C and A728T) and the deletion S965FsX994 were responsible for the deficit in the organification process and the phenotypes. Three polymorphisms (H678R, P982A, and R701Q) were identified.

Details

ISSN :
19457197 and 0021972X
Volume :
96
Database :
OpenAIRE
Journal :
The Journal of Clinical Endocrinology & Metabolism
Accession number :
edsair.doi.dedup.....9cd60d45a681e27523841fd670608c00
Full Text :
https://doi.org/10.1210/jc.2010-2467