先天性甲状腺功能减低DUOXA2基因突变筛查及其分子致病机理研究

DUOXA2和DUOX2基因突变可引起甲状腺激素合成障碍性的先天性甲状腺功能低下（CH）伴甲状腺肿大， DUOXA2对DUOX2功能的成熟起重要辅助功能，相比DUOX2基因，我们对DUOXA2基因突变及其致病机理知之甚少。本研究①拟依托已建立的国内首个大型的CH遗传数据库，以300余例甲状腺肿大的CH 为研究对象，利用变性高效液相层析技术（DHPLC）高通量突变筛选平台进行DUOXA2基因突变筛查，研究中国人群CH常见DUOXA2突变类型和特点，构建基因型与表型关系谱，有利于早期诊断或症状前诊断与产前诊断，达到优生目的。②在前期已发现1个国际首报的DUOXA2基因错义突变(I26M)基础上, 结合本研究拟筛出新突变，研究这些突变对DUOX2酶活性、细胞膜转运、蛋白半衰期及蛋白与蛋白相互作用等影响，进一步揭示DUOXA2基因功能改变导致CH分子致病机理，为CH遗传学干预和治疗提供理存论依据。

DUOX2 and DUOXA2 mutations can cause CH with goiter due to thyroid dyshormonogenesis. DUOXA2 plays an important role in DUOX2 maturation. Compared with DUOX2, very little is yet known of DUOXA2 mutations and its pathogenesis. Firstly, Based on the established domestic largest CH genetic database, this research aimed to investigate DUOXA2 mutations by using the denaturing high performance liquid chromatography (DHPLC), in order to find common mutation types and features of DUOXA2 and confirm the correlations of phenotype-genotype in Chinese CH. It is helpful to early diagnosis, pre-symptomatic diagnosis and prenatal diagnosis of CH, as well as achieving the goal of a healthy pregnancy. Secondly, on the basis of the novel DUOXA2 missense mutation(I26M) we have found and our purpose to identify novel DUOXA2 mutations, we will study the effect of these mutations on DUOX2 activity, cell membrane localization, half-life and protein-protein interactions. Thus, further reveal the pathogenic molecular mechanism of CH due to DUOXA2 mutation and give solid theoretical basis for genetic intervention and therapy of CH.