Communicated by Jurgen Horst.
Mutation in Brief
Compound heterozygosity for a novel hemizygous missense mutation and a partial deletion affecting the catalytic core of the H2O2-generating enzyme DUOX2 associated with transient congenital hypothyroidism†
Article first published online: 25 FEB 2010
© 2010 Wiley-Liss, Inc.
Volume 31, Issue 4, pages E1304–E1319, April 2010
How to Cite
Hoste, C., Rigutto, S., Van Vliet, G., Miot, F. and De Deken, X. (2010), Compound heterozygosity for a novel hemizygous missense mutation and a partial deletion affecting the catalytic core of the H2O2-generating enzyme DUOX2 associated with transient congenital hypothyroidism. Hum. Mutat., 31: E1304–E1319. doi: 10.1002/humu.21227
- Issue published online: 26 MAR 2010
- Article first published online: 25 FEB 2010
- Manuscript Accepted: 2 FEB 2010
- Manuscript Received: 5 NOV 2009
- Cited By
- congenital hypothyroidism;
- thyroid hormone metabolism
Dual oxidases (DUOX) 1 and 2 are components of the thyroid H2O2-generating system. H2O2 is used by thyroperoxidase to oxidize iodide for thyroid hormonogenesis. Mutations in the DUOX2 gene have been described in transient and permanent congenital thyroid dyshormonogenesis. We report here a novel genetic defect causing congenital hypothyroidism in a French-Canadian patient. At neonatal screening, the patient had high TSH and low total T4 levels. 99mTc scan showed a normally shaped orthotopic but mildly enlarged thyroid gland, suggesting dyshormonogenesis. Thyroxine treatment was given from 1 month to 17 years, after which it was stopped for re-evaluation and the patient remained euthyroid. The transient congenital hypothyroidism phenotype prompted us to screen for mutations in DUOX2 and DUOXA2 genes using the PCR-amplified direct sequencing method. We found complete inactivation of DUOX2 caused by a partial genomic deletion of one allele inherited from the mother associated with a paternally inherited missense mutation (c.4552G>A, p.Gly1518Ser). The deleted fragment encompasses the entire COOH-terminal end which is responsible for the NADPH-oxidase activity. The Gly1518Ser DUOX2 protein is expressed at the cell surface of transfected cells albeit at low level, but it is non-functional. This study provides further evidence that the permanent or transient nature of congenital hypothyroidism is not directly related to the number of inactivated DUOX2 alleles, suggesting the existence of other pathophysiological factors. © 2010 Wiley-Liss, Inc.