Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism
Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism
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DOI：
10.1210/jc.2007-2020
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发表时间：
2008-02-01
影响因子：
5.8
通讯作者：
Weber, Giovanna
中科院分区：
文献类型：
--
作者：
Zamproni, Ilaria;Grasberger, Helmut;Weber, Giovanna
背景：双氧化酶2（DUOX 2）是H2 O2发生器的催化核心，在甲状腺激素合成中对甲状腺球蛋白的碘化至关重要。DUOX 2缺乏会导致人类和小鼠先天性甲状腺功能减退症（CH）。我们最近克隆了一个新的基因，目的：我们的目的是确定DUOXA 2突变作为一种新的原因CH由于dyshormonogenesis.患者：受试者包括11例CH患者与部分碘有机化缺陷，但阴性的其他已知遗传原因的部分碘有机化缺陷。一名中国患者出生于非血缘的父母是纯合子的无义突变（p.Y246X），产生一个截短的DUOXA 2蛋白缺乏跨膜螺旋5和C-末端胞质结构域。该突变蛋白在体外重组DUOX 2时无活性。家系分析显示为隐性遗传，因为杂合子携带者甲状腺功能正常，包括新生儿TSH筛查阴性结果。在无关的中国对照组（n = 92）中发现了一个Y246 X杂合子携带者，但在高加索人或日本人对照组中没有发现，表明Y246 X纯合子可能是中国CH的常见原因。功能研究表明，DUOXA 2 paradox（DUOXA 1）可以部分补偿DUOXA 2缺乏，符合先证者有一个温和的CH表型比患者的双等位基因DUOX 2无义mutations.Conclusions：我们报告的第一个突变DUOXA 2，确定在CH和激素异常性甲状腺肿的患者。我们的研究结果为DUOXA 2在甲状腺增生中的关键作用提供了证据。双等位基因DUOXA 2突变是永久性CH中的一种新型遗传事件。
Context: Dual oxidase 2 (DUOX2) is the catalytic core of the H2O2 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.Objective: Our objective was to identify DUOXA2 mutations as a novel cause of CH due to dyshormonogenesis.Patients: Subjects included 11 CH patients with partial iodine organification defect but negative for other known genetic causes of partial iodine organification defect.Results: 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.Conclusions: 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.