Missense mutations in the uromodulin (UMOD) gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. The unknown impact of the allelic and gene dosage effects and fate of mutant uromodulin leaves open the gap between postulated gain-of-function mutations, end-organ damage and disease progression in ADTKD. Based on two prevalent missense UMOD mutations with divergent disease progression, we generated Umod^C171Y and Umod^R186S knock-in mice that showed strong allelic and gene dosage effects on uromodulin aggregates and activation of ER stress and unfolded protein and immune responses, leading to variable kidney damage. Deletion of the wild-type Umod allele in heterozygous Umod^R186S mice increased the formation of uromodulin aggregates and ER stress. Studies in kidney tubular cells confirmed differences in uromodulin aggregates, with activation of mutation-specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased uromodulin aggregates. These studies substantiate the role of toxic aggregates as driving progression of ADTKD-UMOD, relevant for therapeutic strategies to improve clearance of mutant uromodulin.

中文翻译：

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对尿调节素聚集体的等位基因效应导致常染色体显性肾小管间质性肾病

尿调节素 ( UMOD ) 基因的错义突变会导致常染色体显性肾小管间质性肾病 (ADTKD)，这是最常见的单基因肾病之一。突变型尿调节素的等位基因和基因剂量效应以及命运的未知影响，在 ADTKD 中假定的功能获得性突变、终末器官损伤和疾病进展之间打开了差距。基于两种常见的具有不同疾病进展的错义UMOD突变，我们生成了Umod ^C171Y和Umod ^R186S敲入小鼠，它们对尿调节素聚集物以及 ER 应激和未折叠蛋白和免疫反应的激活表现出强烈的等位基因和基因剂量影响，从而导致可变的肾脏损害。杂合子Umod ^R186S小鼠中野生型Umod等位基因的缺失增加了尿调节素聚集体的形成和 ER 应激。对肾小管细胞的研究证实了尿调节素聚集体的差异，并激活了突变特异性质量控制和清除机制。饥饿和 mTORC1 抑制增强自噬可减少尿调节素聚集。这些研究证实了有毒聚集体在驱动 ADTKD- UMOD进展中的作用，与提高突变型尿调节素清除率的治疗策略相关。