{"doi":"10.3389/fgene.2022.1021037","title":"A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease","abstract":"Patient variants in Tubby Like Protein-3 (TULP3) have recently been associated with progressive fibrocystic disease in tissues and organs. TULP3 is a ciliary trafficking protein that links membrane-associated proteins to the intraflagellar transport complex A. In mice, mutations in Tulp3 drive phenotypes consistent with ciliary dysfunction which include renal cystic disease, as part of a ciliopathic spectrum. Here we report two sisters from consanguineous parents with fibrocystic renal and hepatic disease harboring a homozygous missense mutation in TULP3 (NM_003324.5: c.1144C>T, p.Arg382Trp). The R382W patient mutation resides within the C-terminal Tubby domain, a conserved domain required for TULP3 to associate with phosphoinositides. We show that inner medullary collecting duct-3 cells expressing the TULP3 R382W patient variant have a severely reduced ability to localize the membrane-associated proteins ARL13b, INPP5E, and GPR161 to the cilium, consistent with a loss of TULP3 function. These studies establish Arginine 382 as a critical residue in the Tubby domain, which is essential for TULP3-mediated protein trafficking within the cilium, and expand the phenotypic spectrum known to result from recessive deleterious mutations in TULP3 .","journal":"Frontiers in Genetics","year":2022,"id":262468,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"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":456761,"name":"Vivek Reddy Palicharla","orcid":"0000-0002-2478-8045","position":1,"is_corresponding":false},{"id":918226,"name":"Seyed Alireza Dastgheib","orcid":"0000-0003-4781-301X","position":2,"is_corresponding":false},{"id":778355,"name":"Mehdi Dianatpour","orcid":"0000-0003-1217-9477","position":3,"is_corresponding":false},{"id":918227,"name":"Mohammad Hadi Imanieh","orcid":"0000-0003-4610-0413","position":4,"is_corresponding":false},{"id":918228,"name":"Seyed Sajjad Tabei","orcid":"0000-0002-0098-9280","position":5,"is_corresponding":false},{"id":385214,"name":"Whitney Besse","orcid":"0000-0002-8283-1507","position":6,"is_corresponding":false},{"id":277896,"name":"Saikat Mukhopadhyay","orcid":"0000-0003-4790-3090","position":7,"is_corresponding":false},{"id":811249,"name":"Karel F. Liem","orcid":"0000-0002-1566-5561","position":8,"is_corresponding":false},{"id":918225,"name":"Hossein Jafari Khamirani","orcid":"0000-0001-7703-7387","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:26:25.074177Z","pmid":"36276950","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":[]}