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

ABSTRACT: Dual oxidase 2 (DUOX2) is the catalytic core of the H(2)O(2) generator crucial for the iodination of thyroglobulin in thyroid hormone synthesis. DUOX2 deficiency produces congenital hypothyroidism (CH) in humans and mice. We recently cloned a novel gene, the product of which (dual oxidase maturation factor 2; DUOXA2) is required to express DUOX2 enzymatic activity.Our objective was to identify DUOXA2 mutations as a novel cause of CH due to dyshormonogenesis.Subjects included 11 CH patients with partial iodine organification defect but negative for other known genetic causes of partial iodine organification defect.One Chinese patient born to nonconsanguineous parents was homozygous for a nonsense mutation (p.Y246X), producing a truncated DUOXA2 protein lacking transmembrane helix 5 and the C-terminal cytoplasmic domain. The mutant protein was inactive in reconstituting DUOX2 in vitro. Pedigree analysis demonstrated recessive inheritance, because heterozygous carriers had normal thyroid function including negative results in neonatal TSH screening. One heterozygous carrier of Y246X was identified in unrelated Chinese controls (n = 92) but not in Caucasian or Japanese controls, indicating that homozygosity for Y246X could be a frequent cause of CH in Chinese. Functional studies suggest that the DUOXA2 paralog (DUOXA1) can partially compensate DUOXA2 deficiency, consistent with the proband having a milder CH phenotype than patients with biallelic DUOX2 nonsense mutations.We report the first mutation in DUOXA2, identified in a patient with CH and dyshormonogenic goiter. Results of our studies provide evidence for the critical role of DUOXA2 in thyroid hormonogenesis. Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.

SUBMITTER: Zamproni I

PROVIDER: S-EPMC2243227 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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

Zamproni Ilaria I Grasberger Helmut H Cortinovis Francesca F Vigone Maria Cristina MC Chiumello Giuseppe G Mora Stefano S Onigata Kazumichi K Fugazzola Laura L Refetoff Samuel S Persani Luca L Weber Giovanna G

The Journal of clinical endocrinology and metabolism 20071127 2

<h4>Context</h4>Dual oxidase 2 (DUOX2) is the catalytic core of the H(2)O(2) generator crucial for the iodination of thyroglobulin in thyroid hormone synthesis. DUOX2 deficiency produces congenital hypothyroidism (CH) in humans and mice. We recently cloned a novel gene, the product of which (dual oxidase maturation factor 2; DUOXA2) is required to express DUOX2 enzymatic activity.<h4>Objective</h4>Our objective was to identify DUOXA2 mutations as a novel cause of CH due to dyshormonogenesis.<h4> ...[more]

PMID: 18042646

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Project description:Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 (DUOX2) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort. Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6-19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ. DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized. Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 (n = 20; 38%) or DUOXA2 (n = 6; 12%), including novel gene variants (DUOX2, n = 3; DUOXA2, n = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range (M = 9.3 pmol/L, range <3.9-15.8 pmol/L), Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2/DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.

Dataset Information

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

Publications

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

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