包装D1
常染色体显性多囊肾病
多囊肾病
生物
非翻译区
等位基因
囊肿
遗传学
肾
细胞生物学
信使核糖核酸
医学
基因
病理
作者
Ronak Lakhia,Harini Ramalingam,Chun-Mien Chang,Patricia Cobo-Stark,Laurence Biggers,Andrea Flaten,J Alvarez,Tania Valencia,Darren P. Wallace,Edmund C. Lee,Vishal Patel
标识
DOI:10.1038/s41467-022-32543-2
摘要
Abstract Autosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation occurs when PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are repressed via their 3′-UTR miR-17 binding element. Eliminating this motif ( Pkd1 ∆17 ) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also inhibited via its 3′-UTR miR-17 motif, and Pkd2 ∆17 -induced Polycystin-2 derepression retards cyst growth in Pkd1 -mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, modeling PKD1 ∆17 or PKD2 ∆17 alleles in patient-derived primary ADPKD cultures leads to smaller cysts, reduced proliferation, lower pCreb1 expression, and improved mitochondrial membrane potential. Thus, evading 3′-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.
科研通智能强力驱动
Strongly Powered by AbleSci AI