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Here, we investigated the function of S1159F and S1159P, two variants associated with different clinical phenotypes, which affect the same pore\u2010lining residue in transmembrane segment 12 that are both strongly potentiated by ivacaftor when expressed in CFBE41o\n \u2212<\/jats:sup>\n bronchial epithelial cells. To study the single\u2010channel behaviour of CFTR, we applied the patch\u2010clamp technique to Chinese hamster ovary cells heterologously expressing\n CFTR<\/jats:italic>\n variants incubated at 27\u00b0C to enhance channel residence at the plasma membrane. S1159F\u2010 and S1159P\u2010CFTR formed Cl\n \u2212<\/jats:sup>\n channels activated by cAMP\u2010dependent phosphorylation and gated by ATP that exhibited thermostability at 37\u00b0C. Both variants modestly reduced the single\u2010channel conductance of CFTR. By severely attenuating channel gating, S1159F\u2010 and S1159P\u2010CFTR reduced the open probability (\n P<\/jats:italic>\n o<\/jats:sub>\n ) of wild\u2010type CFTR by \u226575% at ATP (1\u00a0mM); S1159F\u2010CFTR caused the greater decrease in\n P<\/jats:italic>\n o<\/jats:sub>\n consistent with its more severe clinical phenotype. Ivacaftor (10\u2013100\u00a0nM) doubled the\n P<\/jats:italic>\n o<\/jats:sub>\n of both\n CFTR<\/jats:italic>\n variants without restoring\n P<\/jats:italic>\n o<\/jats:sub>\n values to wild\u2010type levels, but concomitantly, ivacaftor decreased current flow through open channels. For S1159F\u2010CFTR, the reduction of current flow was marked at high (supersaturated) ivacaftor concentrations (0.5\u20131\u00a0\u03bcM) and voltage\u2010independent, identifying an additional detrimental action of elevated ivacaftor concentrations. In conclusion, S1159F and S1159P are gating variants, which also affect CFTR processing and conduction, but not stability, necessitating the use of combinations of CFTR modulators to optimally restore their channel activity.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Dysfunction of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes the genetic disease cystic fibrosis (CF).<\/jats:p>\n <\/jats:list-item>\n \n \n This study investigated two rare pathogenic\n CFTR<\/jats:italic>\n variants, S1159F and S1159P, which affect the same amino acid in CFTR, to understand the molecular basis of disease and response to the CFTR\u2010targeted therapy ivacaftor.\n <\/jats:p>\n <\/jats:list-item>\n \n Both rare variants diminished CFTR function by modestly reducing current flow through the channel and severely inhibiting ATP\u2010dependent channel gating with S1159F exerting the stronger adverse effect, which correlates with its association with more severe disease.<\/jats:p>\n <\/jats:list-item>\n \n Ivacaftor potentiated channel gating by both rare variants without restoring their activity to wild\u2010type levels, but concurrently reduced current flow through open channels, particularly those of S1159F\u2010CFTR.<\/jats:p>\n <\/jats:list-item>\n \n Our data demonstrate that S1159F and S1159P cause CFTR dysfunction by multiple mechanisms that require combinations of CFTR\u2010targeted therapies to fully restore channel function.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp285727","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T02:39:31Z","timestamp":1704681571000},"page":"333-354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Two rare variants that affect the same amino acid in CFTR have distinct responses to ivacaftor"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5405-9401","authenticated-orcid":false,"given":"Hongyu","family":"Li","sequence":"first","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2062-8682","authenticated-orcid":false,"given":"Mayuree","family":"Rodrat","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol Bristol UK"},{"name":"Center of Research and Development for Biomedical Instrumentation, Institute of Molecular Biosciences Mahidol University Nakhon Pathom Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1909-0141","authenticated-orcid":false,"given":"Majid K.","family":"Al\u2010Salmani","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol Bristol UK"},{"name":"Department of Physiology, College of Medicine and Health Sciences Sultan Qaboos University Al Khoudh, Muscat Sultanate of Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-1326","authenticated-orcid":false,"given":"Diana\u2010Florentina","family":"Veselu","sequence":"additional","affiliation":[{"name":"School of Biochemistry University of Bristol Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5876-704X","authenticated-orcid":false,"given":"Sangwoo T.","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine Johns Hopkins University School of Medicine Baltimore Maryland 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