Zebrafish duox mutations provide a model for human congenital hypothyroidism
Zebrafish duox mutations provide a model for human congenital hypothyroidism
复制标题
DOI：
10.1242/bio.037655
复制
发表时间：
2019-02-01
期刊：
影响因子：
2.4
通讯作者：
Amaya, Enrique
中科院分区：
文献类型：
--
作者：
Chopra, Kunal;Ishibashi, Shoko;Amaya, Enrique
甲状腺激素生成障碍是先天性甲状腺功能减退症的主要原因，这是一种非常普遍但可治疗的疾病。甲状腺激素（TH）的合成依赖于活性氧（ROS）的形成。在人类中，在甲状腺激素合成过程中产生ROS的主要来源是NADPH氧化酶DUOX1和DUOX2。事实上，DUOX1和DUOX2的突变与先天性甲状腺功能减退有关。与人类不同，斑马鱼有单一的DUOX1和DUOX2同源物。在本研究中，我们研究了斑马鱼单双氧基因中两个无义突变等位基因sa9892和sa13017的相关表型。从幼虫期到成年期，这两个等位基因都产生了容易观察到的表型，使人联想到先天性甲状腺功能减退症。通过使用各种方法检查外部和内部表型，我们发现TH合成与duox功能之间存在很强的相关性。从早期幼虫阶段开始，当T-4水平在突变体中已经明显缺失时。T-4产量的减少导致生长迟缓、色素沉着缺陷、鱼鳍粗糙、甲状腺增生/外甲状腺肿和不育。值得注意的是，所有这些与慢性先天性甲状腺功能减退相关的缺陷都可以通过T-4治疗得到修复，即使是在鱼已经成年的时候。我们的工作表明，这些斑马鱼二重突变体可能为理解未经治疗和治疗的先天性甲状腺功能减退症的病因提供了一个强有力的模型，即使是在发展的晚期。本文以第一人称采访了该论文的第一作者。
Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone (TH) synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidases DUOX1 and DUOX2. Indeed, mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2. In this study, we investigated the phenotypes associated with two nonsense mutant alleles, sa9892 and sa13017, of the single duox gene in zebrafish. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function. beginning from an early larval stage, when T-4 levels are already noticeably absent in the mutants. Loss of T-4 production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia/external goiter and infertility. Remarkably, all of these defects associated with chronic congenital hypothyroidism could be rescued with T-4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advanced stages of development.This article has an associated First Person interview with the first author of the paper.