An exonic splicing enhancer mutation in DUOX2 causes aberrant alternative splicing and severe congenital hypothyroidism in Bama pigs
An exonic splicing enhancer mutation in DUOX2 causes aberrant alternative splicing and severe congenital hypothyroidism in Bama pigs
复制标题
DUOX2 中的外显子剪接增强子突变会导致巴马猪异常剪接和严重的先天性甲状腺功能减退症。
DOI：
10.1242/dmm.036616
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发表时间：
2019-01-01
影响因子：
4.3
通讯作者：
Zhao, Jianguo
中科院分区：
文献类型：
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作者：
Cao, Chunwei;Zhang, Ying;Zhao, Jianguo
猪在解剖学、生理学和遗传学方面与人类有许多相似之处，长期以来一直被认为是生物医学研究中的重要实验动物。利用N-乙基-N-亚硝脲(ENU)诱变筛选，我们先前鉴定了大量的猪突变株，可以进一步建立人类疾病模型。然而，在具有极大异质性的大型动物中鉴定致病突变仍然是一项具有挑战性的努力。在这里，我们选择了一头猪突变体，表现为先天性裸露皮肤和甲状腺功能缺陷，呈隐性遗传模式。我们能够使用基于家族的全基因组关联研究，结合全外显子组测序和小样本大小，有效地定位致病突变。在DUOX2基因中发现了一个功能缺失的变异体(c.1226A>；G)，导致高度保守的氨基酸替换(D409G)。该突变位于外显子剪接增强子基序中，导致DUOX2转录本的异常剪接，导致过氧化氢产生减少，这可能导致甲状腺激素产生的严重缺陷。我们的发现表明，外显子组测序是定位致病突变的有效方法，DUOX2(D409G/D409G)突变猪可能是一种潜在的人类先天性甲状腺功能减退的大型动物模型。
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.