Novel non-synonymous mutations of PAX8 in a cohort of Chinese with congenital hypothyroidism  

作　　者：Fang Qian Gui-Yu Li Xiang-Jun Wu Qin Jia Guan-Ting Lyu Man-Li Wang Jun Wang 

机构地区：[1]Department of Genetics, Reproductive Health Hospital of Xinjiang Uygur Autonomous Region, Urumchi, Xinjiang 830011, China [2]Department of Global Health, College of Health, Wuhan University, Wuhan, Hubei 430072, China [3]Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China [4]Department of Neurology, Guanghang People's Hospital, Deyang, Sichuan 618300, China [5]Department of Pathology, Guanghang People's Hospital, Deyang, Sichuan 618300, China [6]Department of Blood Transfusion, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China [7]Department of Clinic Laboratory, Reproductive Health Hospital of Xinjiang Uygur Autonomous Region, Urumchi, Xinjiang 830011, China

出　　处：《Chinese Medical Journal》2019年第11期1322-1327,共6页中华医学杂志（英文版）

基　　金：National Natural Science Foundation of China (No.81101490).

摘　　要：Background:The transcription factor paired box 8 (PAX8) was associated with type 2 congenital non-goitrous hypothyroidism (CHNG2), a clinical phenotype of congenital hypothyroidism (CH). Though studied in a few regions with different ethnicities, the incidence of PAX8 mutations varied, even among Chinese cohorts in different regions. This study aimed to identify and characterize PAX8 mutations and explore the prevalence of its mutations in another cohort of CH. Methods: The 105 unrelated Chinese patients with CH were collected from four major hospitals. Exomes of the 105 samples were sequenced by Hiseq 2000 platform to identify mutations of PAX8 on genomic DNAs extracted from peripheral blood samples. Luciferase reporter assays were used to assess the effects of mutations on the transcription of thyroid peroxidase (TPO). Results: Three PAX8 mutations in four subjects were identified in 105 samples. One variant, rsl 89229644, was detected in two subjects, and categorized as uncertain significance. The other two missense mutations (275T>C/Ile92Thr and 398G>A/Argl33Gln) were not detected in three large-scale genotyping projects, namely 1000 Genome Project, Exome Aggregation Consortium and GO Exome Sequencing Project. Functional studies for the two mutations revealed that they could impair the transcription ability of PAX8 on one of its target genes, TPO. Therefore, the two mutations were causative for the pathogenesis of CHNG2. After combining the studies of PAX8 mutations, an average frequency of 1.74%(21/1209) could be obtained in Chinese patients with CH. Conclusion: The study specifically demonstrates the role of two mutations in impairing the transcription ability of PAX8, which should be considered as pathogenic variants for CH.

关 键 词：CONGENITAL HYPOTHYROIDISM Paired box 8 NOVEL non-synonymous mutation Transcription factor 

分 类 号：R[医药卫生]