{"doi":"10.1101/2022.02.23.479396","title":"<i>PKD1</i> and <i>PKD2</i> mRNA cis-inhibition drives polycystic kidney disease progression","abstract":"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 ensues when the 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 cis-repressed via their 3’-UTR miR-17 binding element. Eliminating this motif ( Pkd1 Δ17 ) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo , and mouse PKD models. Remarkably, Pkd2 is also autoinhibited via its 3’-UTR miR-17 motif, and Pkd2 Δ17 -induced Polycystin-2 derepression partly compensates and retards cyst growth in Pkd1 -mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, PKD1 Δ17 or PKD2 Δ17 alleles revert cyst-pathogenic sequala in patient-derived primary ADPKD cultures. Thus, evading 3’-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":306094,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":314839,"name":"Harini Ramalingam","orcid":"0000-0001-7029-9069","position":1,"is_corresponding":false},{"id":639578,"name":"Chun-Mien Chang","orcid":null,"position":2,"is_corresponding":false},{"id":638612,"name":"Patricia Cobo-Stark","orcid":"0000-0002-8113-6211","position":3,"is_corresponding":false},{"id":314842,"name":"Laurence Biggers","orcid":"0000-0001-8514-9549","position":4,"is_corresponding":false},{"id":314838,"name":"Andrea Flaten","orcid":"0000-0001-9975-837X","position":5,"is_corresponding":false},{"id":855676,"name":"Jesus Alvarez","orcid":null,"position":6,"is_corresponding":false},{"id":855677,"name":"Tania Valencia","orcid":null,"position":7,"is_corresponding":false},{"id":299686,"name":"Darren P. Wallace","orcid":"0000-0003-4616-7669","position":8,"is_corresponding":false},{"id":1000030,"name":"Edmund Lee","orcid":"0000-0001-9112-4460","position":9,"is_corresponding":false},{"id":314845,"name":"Vishal Patel","orcid":"0000-0003-2875-4659","position":10,"is_corresponding":false},{"id":314836,"name":"Ronak Lakhia","orcid":"0000-0002-4511-5341","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T00:32:44.983506Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}