Liu Shiguo, Han Wenxiu, Zang Yucui, Zang Hongwei, Wang Fang, Jiang Pei, Wei Hongwei, Liu Xiangju, Wang Yangang, Ma Xu, Ge Yinlin
Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, China.
Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
Front Endocrinol (Lausanne). 2019 Aug 2;10:526. doi: 10.3389/fendo.2019.00526. eCollection 2019.
The DUOX/DUOXA systems play a key role in HO generation in thyroid cells, which is required for iodine organification and thyroid hormone synthesis. DUOX2/DUOXA2 defects can cause congenital hypothyroidism (CH), but it is unknown whether mutations can also cause CH. We aimed to identify mutations and explore their role in the development of CH by investigating their functional impacts on HO generation. Forty-three children with CH with goiter were enrolled, in whom all exons and flanking intronic regions of were directly sequenced. We characterized the functional effects of identified mutations on the expression of and and HO generation. We identified a heterozygous missense mutation (G > A base substitution at nucleotide 3920 in exon 31) that changed a highly conserved arginine to glutamine at residual 1307 (p.R1307Q) in patient 1. A heterozygous-missense mutation (c.166 C>T; p.R56W) was identified in in patient 2. Functional studies demonstrated that both p.R1307Q mutant or p.R56W mutant decreased the expression at mRNA and protein levels, with a corresponding impairment in HO generation ( < 0.01). The results also showed that intact DUOXA1 was required for full activity of DUOX1 and HO generation. We have identified two heterozygous missense mutations in and in two patients that can cause CH through disrupting the coordination of DUOX1 and DUOXA1 in the generation of HO. This study for the first time demonstrates that the DUOX1/DUOXA1 system, if genetically defective, can cause CH.
DUOX/DUOXA系统在甲状腺细胞中过氧化氢（HO）生成过程中起关键作用，而HO生成是碘有机化和甲状腺激素合成所必需的。DUOX2/DUOXA2缺陷可导致先天性甲状腺功能减退症（CH），但尚不清楚DUOX1基因突变是否也会导致CH。我们旨在通过研究DUOX1基因突变对HO生成的功能影响来鉴定这些突变，并探讨它们在CH发生发展中的作用。招募了43例患有甲状腺肿大的CH患儿，对其DUOX1基因的所有外显子和侧翼内含子区域进行直接测序。我们对鉴定出的突变对DUOX1和DUOXA1表达以及HO生成的功能影响进行了表征。在患者1中，我们鉴定出一个杂合错义突变（第31外显子核苷酸3920处G>A碱基替换），该突变导致第1307位残基处一个高度保守的精氨酸变为谷氨酰胺（p.R1307Q）。在患者2的DUOX1基因中鉴定出一个杂合错义突变（c.166 C>T；p.R56W）。功能研究表明，p.R1307Q突变体或p.R56W突变体均在mRNA和蛋白质水平降低了DUOX1的表达，同时HO生成相应受损（P<0.01）。结果还表明，完整的DUOXA1是DUOX1充分发挥活性和HO生成所必需的。我们在两名患者的DUOX1基因中鉴定出两个杂合错义突变，它们可通过破坏DUOX1和DUOXA1在HO生成过程中的协调作用而导致CH。这项研究首次证明，DUOX1/DUOXA1系统若存在基因缺陷可导致CH。
