{"doi":"10.1074/jbc.ra120.013943","title":"Kidney-disease-associated variants of Apolipoprotein L1 show gain of function in cation channel activity","abstract":"Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately twofold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared with the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles. Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately twofold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared with the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles. Two distinct variants in the protein ApoL1 are known to be responsible for the recognized increased risk of progressive proteinuric kidney disease in people of African ancestry, particularly due to focal segmental glomerulosclerosis, hypertensive nephrosclerosis, and HIV-associated nephropathy (1Genovese G. Friedman D.J. Ross M.D. Lecordier L. Uzureau P. Freedman B.I. Bowden D.W. Langefeld C.D. Oleksyk T.K. Uscinski Knob A.L. Bernhardy A.J. Hicks P.J. Nelson G.W. Vanhollebeke B. Winkler C.A. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1217) Google Scholar, 2Parsa A. Kao W.H. Xie D. Astor B.C. Li M. Hsu C.Y. Feldman H.I. Parekh R.S. Kusek J.W. Greene T.H. Fink J.C. Anderson A.H. Choi M.J. Wright Jr., J.T. Lash J.P. et al.APOL1 risk variants, race, and progression of chronic kidney disease.N. Engl. J. Med. 2013; 369: 2183-2196Crossref PubMed Scopus (460) Google Scholar, 3Friedman D.J. Pollak M.R. APOL1 and kidney disease: From genetics to biology.Annu. Rev. Physiol. 2020; 82: 323-342C","journal":"Journal of Biological Chemistry","year":2020,"id":77093,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9427,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":401922,"name":"John C. Edwards","orcid":"0000-0002-0500-716X","position":1,"is_corresponding":false},{"id":403298,"name":"Jonathan Bruno","orcid":null,"position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-18T21:48:50.085103Z","pmid":"33380423","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":[]}