First identification of a mutation in the DUOXA2 gene, in a Chinese patient with CH due to a partial iodine organification defect

TOPIC: D yshormonogenesis due to mutations in DUOXA2 gene

Title: Biallelic inactivation of the dual oxidase maturation factor 2 ( DUOXA2 ) gene as a novel cause of congenital hypothyroidism.

Authors: Zamproni I, Grasberger H, Cortinovis F, Vigone MC, Chiumello G, Mora S, Onigata K, Fugazzola L, Refetoff S, Persani L, & Weber G.

Reference: Journal of Clinical Endocrinology & Metabolism (ahead of print) November 27, 2007



Dual oxidase 2 (DUOX2) is the catalytic core of the H 2 O 2 generating system which is crucial for iodination of thyroglobulin and thyroid hormone synthesis. DUOX2 deficiency is known to produce congenital hypothyroidism (CH) in humans and mice. It has recently been reported that the expression of active DUOX2 at the apical plasma membrane of thyrocytes requires a protein named DUOXA2, a type of molecular 'chaperon' encoded by a gene located in the DUOX1 / DUOX2 intergenic region.


The authors investigated the possibility of thyroid dyshormonogenesis linked to mutations in the DUOXA2 gene.


The search for mutation(s) of the DUOXA2 gene was conducted on a series of eleven patients with partial iodine organification defect (PIOD) found to be negative for the other known genetic alterations causing PIOD. These patients had normal or high serum Tg level, no hearing impairment (no pendrin or SLC26A4 mutation), no detectable TPO or DUOX2 mutations.


Expression and functional analyses of wild type and mutated form(s) of DUOXA2 performed in HeLa cells.


Among 11 patients with idiopathic PIOD, 1 chinese girl born to non-consanguineous parents exhibited a homozygous C ' G transversion in codon 246, resulting in a nonsense mutation (Y246X). The mutation is expected to lead to the synthesis of a truncated DUOXA2 protein, lacking the last transmembrane domain -helix 5- and the C terminal cytoplasmic domain. Parents and sisters of the proband were heterozygous carriers (C/G) of the mutation and had normal thyroid function parameters. The mutated DUOXA2 gene expressed in HeLa cells yielded a ~30 kDa glycosylated polypeptide chain instead of the 35-37 kDa native glycoprotein. The 246X mutant protein was N-glycosylated to the same degree as wild type DUOXA2, but its expression was reduced compared to that of normal DUOXA2. Wild-type DUOXA2 showed a dispersed distribution in endoplasmic reticulum, whereas the 246X protein appeared concentrated in foci in the vicinity of the nuclear envelope. Function of the mutated DUOXA2 was studied by DUOX2/DUOXA2 reconstitution experiments in HeLa cells and measurement of H 2 O 2 production. Co-expression of DUOX2 and wild type DUOXA2 in HeLa cells led to expression of a DUOX protein producing H 2 O 2 . In contrast, co-expression of DUOX2 and 246X DUOXA2 did not reconstitute DUOX2 activity. Genotyping of unrelated control individuals revealed one heterozygous carrier of the Y246X mutation in 92 Chinese individuals; the mutation was not detected in controls of subjects of Caucasian (178 alleles) or Japanese (82 alleles) ethnicity.


This article reports the first mutation in DUOXA2 in a patient with CH. Pedigree analysis demonstrate recessive inheritance. Biallelic DUOXA2 mutations are thus a novel genetic event in permanent CH.


Molecular studies of DUOX proteins have been hampered for a number of years by the failure to reconstitute active DUOX enzymes in heterologous systems. For unknown reasons, recombinant DUOX was completely retained inside the endoplasmic reticulum (ER) in an immature form. In 2006, Sam Refetoff and coll. provided the answer, by discovering factors ( DUOXA1 & DUOXA2 ) that are specifically involved in the maturation of DUOX1/DUOX2 proteins. The authors found that it was possible to reconstitute a DUOX-based H 2 O 2 generating system in transfected cells, if cells co-expressed a DUOX gene and the respective DUOXA1 or DUOXA2 genes. DUOXA2 allows the exit of folded DUOX2 from ER to the Golgi apparatus. DUOXA2 may be part of a quality control system specific for DUOX2. In the present article, the native form of the DUOX2 maturation factor DUOXA2 was shown to be necessary and sufficient for expression of functional DUOX2 in a mammalian cell line.

Screening 11 patients with PIOD, the authors were able to find one demonstrative case: a bi-allelic mutation of the DUOXA2 gene in a Chinese patient leading to a complete loss of function of the protein in this patient. The truncated protein appears to be subjected to degradation at the site of synthesis. This study provides evidence for a critical role of DUOXA2 in thyroid hormonogenesis. Search for DUOXA2 mutation in control patients of different ethnic origins led the authors to suggest that homozygosity for the Y246X mutation could be a rather frequent cause of CH in Chinese subjects.

Summary and commentary prepared by Bernard Rousset (related to Chapter 2 of TDM) Full paper obtainable at:

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