Zhang Hai-Yang, Zhang Cao-Xu, Wu Feng-Yao, Wu Chen-Yang, Zhang Fei-Yang, Yang Liu, Zhang Yue, Song Huai-Dong, Zhao Shuang-Xia
The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics and Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai 200011, China.
Department of Respiratory and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Eur J Endocrinol. 2025 Jun 30;193(1):21-30. doi: 10.1093/ejendo/lvaf123.
Dual oxidase maturation factor 2 (DUOXA2) is necessary for proper cellular localization and maturation of functional dual oxidase 2 (DUOX2). It is an attractive candidate gene for congenital hypothyroidism (CH). This study aimed to identify DUOXA2 variants in Chinese CH patients, analyze the function of the variants, and explore the genotype-phenotype relationship.
A total of 599 patients with CH were recruited for screening DUOXA2 variants by performing targeted next-generation sequencing or whole exome sequencing. Detailed clinical data were collected for statistical analysis. The biological function of the identified DUOXA2 variants was detected in vitro.
A total of 13 variants including 6 novel variants were detected in the DUOXA2 gene, showing a 6.7% rate in variant carrying (40/599). Ten variants disrupted the enzyme activity of DUOX2, resulting in impaired H2O2 production. In addition, we found that oligogenic mutation patterns within the DUOX system were prevalent among Chinese patients with CH. The cases in the DUOXA2-mutated group were milder and more likely to manifest as normal thyroid size than those in the nonmutated group.
Our study greatly expanded the variant spectrum of the DUOXA2 gene. Pedigree and in vitro functional studies improved the accuracy of genetic counseling. The genotype-phenotype relationship of DUOXA2 broadened the understanding of the CH phenotype spectrum.
双氧化酶成熟因子2（DUOXA2）对于功能性双氧化酶2（DUOX2）的正确细胞定位和成熟是必需的。它是先天性甲状腺功能减退症（CH）的一个有吸引力的候选基因。本研究旨在鉴定中国CH患者中的DUOXA2变异体，分析这些变异体的功能，并探索基因型与表型的关系。
共招募了599例CH患者，通过靶向二代测序或全外显子组测序筛选DUOXA2变异体。收集详细的临床数据进行统计分析。在体外检测已鉴定的DUOXA2变异体的生物学功能。
在DUOXA2基因中总共检测到13个变异体，包括6个新变异体，携带变异体的比例为6.7%（40/599）。10个变异体破坏了DUOX2的酶活性，导致过氧化氢生成受损。此外，我们发现DUOX系统内的寡基因突变模式在中国CH患者中很普遍。DUOXA2突变组的病例比未突变组的病情较轻，且更有可能表现为甲状腺大小正常。
我们的研究极大地扩展了DUOXA2基因的变异谱。家系和体外功能研究提高了遗传咨询的准确性。DUOXA2的基因型与表型关系拓宽了对CH表型谱的认识。
