An exonic splicing enhancer mutation in DUOX2 causes aberrant alternative splicing and severe congenital hypothyroidism in Bama pigs

文献类型： 外文期刊

第一作者： Cao, Chunwei

作者： Cao, Chunwei;Zhang, Ying;Jia, Qitao;Wang, Xiao;Zheng, Qiantao;Zhang, Hongyong;Song, Ruigao;Li, Yongshun;Luo, Ailing;Hong, Qianlong;Qin, Guosong;Yao, Jing;Zhang, Nan;Wang, Hongmei;Zhou, Qi;Zhao, Jianguo;Cao, Chunwei;Zhang, Ying;Jia, Qitao;Wang, Xiao;Zheng, Qiantao;Zhang, Hongyong;Song, Ruigao;Luo, Ailing;Hong, Qianlong;Qin, Guosong;Yao, Jing;Zhang, Nan;Wang, Hongmei;Zhou, Qi;Zhao, Jianguo;Li, Yongshun;Wang, Yanfang

作者机构：

关键词： Pigs; Animal model; ENU; Exome sequencing; Congenital hypothyroidism

期刊名称：DISEASE MODELS & MECHANISMS （ 影响因子：5.758； 五年影响因子：6.479 ）

ISSN： 1754-8403

年卷期： 2019 年 12 卷 1 期

页码：

收录情况： SCI

摘要： Pigs share many similarities with humans in terms of anatomy, physiology and genetics, and have long been recognized as important experimental animals in biomedical research. Using an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we previously identified a large number of pig mutants, which could be further established as human disease models. However, the identification of causative mutations in large animals with great heterogeneity remains a challenging endeavor. Here, we select one pig mutant, showing congenital nude skin and thyroid deficiency in a recessive inheritance pattern. We were able to efficiently map the causative mutation using family-based genome-wide association studies combined with whole-exome sequencing and a small sample size. A loss-of-function variant (c.1226 A>G) that resulted in a highly conserved amino acid substitution (D409G) was identified in the DUOX2 gene. This mutation, located within an exonic splicing enhancer motif, caused aberrant splicing of DUOX2 transcripts and resulted in lower H2O2 production, which might cause a severe defect in thyroid hormone production. Our findings suggest that exome sequencing is an efficient way to map causative mutations and that DUOX2(D409G/D409G) mutant pigs could be a potential large animal model for human congenital hypothyroidism.

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