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A mouse model of Waardenburg syndrome type IV resulting from an ENU-induced mutation in endothelin 3

机译:ENU诱导的内皮素3突变导致的Waardenburg综合征IV型小鼠模型

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A line of mutant mice (114-CH19) exhibiting white spotting and preweaning lethality was identified during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. The trait segregated as a semidominant bellyspot with reduced penetrance. Homozygous mutant mice showed preweaning lethality, and exhibited white spotting over the majority of the body surface, with pigmented patches remaining around the pinnae, eyes and tail. Linkage analysis localized 114-CH19 on mouse chromosome 2, suggesting endothelin 3 (Edn3) as a candidate gene. Sequence analysis of Edn3 identified a G > A transversion that encodes an arginine to histidine substitution (R96H). This mutation is predicted to disrupt furin-mediated proteolytic cleavage of pro-endothelin that is necessary to form biologically active EDN3. This mutation is novel among human and mouse EDN3 mutants, is the first reported EDN3 ENU mutant, and is the second reported EDN3 point mutation. This study demonstrates the power of using ENU mutagenesis screens to generate new animal models of human disease, and expands the spectrum of EDN3 mutant alleles.
机译:在N-乙基-N-亚硝基脲(ENU)诱变筛选过程中,鉴定出一系显示白色斑点和断奶前致死率的突变小鼠(114-CH19)。性状分离为半显性肚pot,外et减少。纯合突变小鼠表现出断奶前的致死率,并且在体表的大部分区域显示出白色斑点,并且在耳廓,眼睛和尾巴周围残留有色素斑。连锁分析将114-CH19定位在小鼠2号染色体上,提示内皮素3(Edn3)为候选基因。 Edn3的序列分析确定了一个G> A反转,该反转编码一个精氨酸向组氨酸的取代(R96H)。预计该突变将破坏弗林蛋白酶介导的内皮素的蛋白水解切割,这是形成生物活性EDN3所必需的。该突变在人和小鼠EDN3突变体中是新颖的,是第一个报道的EDN3 ENU突变体,也是第二个报道的EDN3点突变。这项研究证明了使用ENU诱变筛选产生人类疾病的新动物模型的能力,并扩展了EDN3突变等位基因的范围。

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