对艾伦 - 赫恩登 - 达德利综合征的进一步见解：一种新型MCT8突变的临床和功能特征
Further Insights into the Allan-Herndon-Dudley Syndrome: Clinical and Functional Characterization of a Novel MCT8 Mutation.
作者信息
Armour Christine M, Kersseboom Simone, Yoon Grace, Visser Theo J
机构信息
Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
出版信息
PLoS One. 2015 Oct 1;10(10):e0139343. doi: 10.1371/journal.pone.0139343. eCollection 2015.
BACKGROUND
Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization.
METHODS
Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter.
RESULTS
The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells.
CONCLUSIONS
We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction.
背景
甲状腺激素（TH）转运体MCT8的突变已被确定为艾伦 - 赫恩登 - 达德利综合征（AHDS）的病因，其特征为严重的精神运动发育迟缓以及血清TH水平改变。在此，我们报告在一个家族的四代人中鉴定出的一种新型MCT8突变及其功能特征。
方法
对先证者和家庭成员进行与X连锁认知障碍相关的60个基因的筛查，并确认MCT8突变。通过分析成纤维细胞、瞬时转染的JEG3和COS1细胞中[125I]TH的转运，以及转运体的亚细胞定位，研究MCT8突变的功能后果。
结果
先证者和一名男性表亲表现出AHDS的临床特征。血清分析显示先证者的T3水平高、rT3水平低，T4和TSH水平正常。在先证者、其表亲和几名女性携带者中鉴定出一种MCT8突变（c.869C>T；p.S290F）。对S290F突变体的功能分析表明，在三种细胞类型中TH转运、代谢和蛋白质表达均降低，而S290A突变则无影响。有趣的是，与他健康的兄弟相比，先证者成纤维细胞中T3和T4的摄取和流出均受损。然而，未观察到S290F突变对COS1和JEG3细胞中TH流出的影响。免疫细胞化学显示野生型MCT8以及S290A和S290F突变体在JEG3细胞中的质膜定位。
结论
我们描述了一个患有艾伦 - 赫恩登 - 达德利综合征家族四代人中的一种新型MCT8突变（S290F）。功能分析表明MCT8转运体功能丧失。此外，我们的结果表明S290F突变体的功能取决于细胞环境。S290F和S290A突变体的比较表明，导致S290F功能障碍的不是丝氨酸的缺失，而是其被苯丙氨酸取代。
Zotero 插件