A Single Copy of the Recently Identified Dual Oxidase Maturation Factor (DUOXA) 1 Gene Produces Only Mild Transient Hypothyroidism in a Patient with a Novel Biallelic DUOXA2 Mutation and Monoallelic DUOXA1 Deletion
A Single Copy of the Recently Identified Dual Oxidase Maturation Factor (DUOXA) 1 Gene Produces Only Mild Transient Hypothyroidism in a Patient with a Novel Biallelic DUOXA2 Mutation and Monoallelic DUOXA1 Deletion
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DOI：
10.1210/jc.2010-2321
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发表时间：
2011-05-01
影响因子：
5.8
通讯作者：
Grasberger, Helmut
中科院分区：
文献类型：
--
作者：
Hulur, Imge;Hermanns, Pia;Grasberger, Helmut
内容：双氧化酶（DUOX 1和DUOX 2）在碘氧化和甲状腺激素合成所需的过氧化氢的产生中起着至关重要的作用。与特异性成熟因子（DUOXA 1和DUOXA 2）的异源二聚化对于DUOX酶复合物的成熟和功能至关重要。DUOX 2的双等位基因功能丧失突变导致先天性甲状腺功能减退症（CH），而单一报道的纯合子DUOXA 2突变（Y246 X）病例与轻度CH相关。目的：我们现在报告一例由于DUOX/DUOXA系统复杂的遗传改变而导致短暂CH的婴儿。我们的病人出生于甲状腺功能正常的非血缘父母，并提出了一个升高的TSH和甲状腺肿大的新生儿筛查。遗传学分析显示母亲DUOXA 2等位基因上存在错义突变（C189 R）。突变体DUOXA 2蛋白在体外重建DUOX 2时显示出完全丧失功能。先证者的C189 R纯合性在父亲没有相同的突变导致详细的基因定位，揭示了一个约43 kb的对缺失，包括DUOX 2，DUOXA 1和DUOXA 2。因此，除了在DUOXA 2缺陷，先证者缺乏DUOXA 2和DUOXA 1的一个等位基因，但有两个功能DUOXA 1 allele.Conclusion：在只有一个功能成熟因子等位基因的存在下，瞬时CH表明在DUOX/DUOXA系统的功能冗余的高水平。（临床内分泌代谢杂志96：E841-E845，2011）
Context: Dual oxidases (DUOX1 and DUOX2) play a crucial role in the generation of hydrogen peroxide required in the oxidation of iodide and the synthesis of thyroid hormone. Heterodimerization with specific maturation factors (DUOXA1 and DUOXA2) is essential for the maturation and function of the DUOX enzyme complexes. Biallelic loss-of-function mutations of DUOX2 result in congenital hypothyroidism (CH), whereas a single reported case of homozygous DUOXA2 mutation (Y246X) has been associated with mild CH.Objective: We now report an infant with transient CH due to a complex genetic alteration of the DUOX/DUOXA system.Results: Our patient was born to euthyroid nonconsanguineous parents and presented with an elevated TSH and enlarged thyroid gland at neonatal screening. Genetic analysis revealed a missense mutation (C189R) on the maternal DUOXA2 allele. The mutant DUOXA2 protein showed complete loss-of-function in reconstituting DUOX2 in vitro. The apparent C189R homozygosity of the proband in the absence of the same mutation in the father led to detailed gene mapping, revealing an approximately 43-kb pair deletion encompassing DUOX2, DUOXA1, and DUOXA2. Thus, in addition to being deficient in DUOXA2, the proband lacks one allele of DUOX2 and DUOXA1 but has two functioning DUOX1 alleles.Conclusion: The transient CH in the presence of only one functional maturation factor allele indicates a high level of functional redundancy in the DUOX/DUOXA system. (J Clin Endocrinol Metab 96: E841-E845, 2011)