An exonic splicing enhancer mutation in <i>DUOX2</i> causes aberrant alternative splicing and severe congenital hypothyroidism in Bama pigs
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- Chunwei Cao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Ying Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Qitao Jia
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Xiao Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Qiantao Zheng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Hongyong Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Ruigao Song
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Yongshun Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Ailing Luo
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Qianlong Hong
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Guosong Qin
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Jing Yao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Nan Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Yanfang Wang
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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- Hongmei Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
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- Jianguo Zhao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
抄録
<jats:title>ABSTRACT</jats:title> <jats:p>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 DUOX2D409G/D409G mutant pigs could be a potential large animal model for human congenital hypothyroidism.</jats:p>
収録刊行物
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- Disease Models & Mechanisms
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Disease Models & Mechanisms 12 (1), dmm036616-, 2019-01-01
The Company of Biologists
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キーワード
詳細情報 詳細情報について
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- CRID
- 1360857596885790976
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- ISSN
- 17548411
- 17548403
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- データソース種別
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- Crossref