{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:03:20Z","timestamp":1784027000389,"version":"3.55.0"},"reference-count":59,"publisher":"American Society for Clinical Investigation","issue":"6","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK44003"],"award-info":[{"award-number":["R01DK44003"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"crossref","award":["CUTTIN13A1,CUTTIN5XX0,CUTTIN16IO,GORALS19Y5,Bridge18XX0"],"award-info":[{"award-number":["CUTTIN13A1,CUTTIN5XX0,CUTTIN16IO,GORALS19Y5,Bridge18XX0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006501","name":"Cystic Fibrosis Foundation Therapeutics","doi-asserted-by":"crossref","award":["SHEPPA14XX0"],"award-info":[{"award-number":["SHEPPA14XX0"]}],"id":[{"id":"10.13039\/100006501","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,22]]},"abstract":"<jats:p>\n                    The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (\n                    <jats:italic>CFTR<\/jats:italic>\n                    ) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    ]; 87\u2013105 mEq\/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    ] (75\u2013123 mEq\/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% \u00b1 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o\n                    <jats:sup>\u2013<\/jats:sup>\n                    ) cells, F312del-CFTR demonstrated residual function (50.9% \u00b1 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.148841","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T14:00:57Z","timestamp":1647871257000},"source":"Crossref","is-referenced-by-count":10,"title":["CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6730-6854","authenticated-orcid":true,"given":"Karen S.","family":"Raraigh","sequence":"first","affiliation":[{"name":"Johns Hopkins University, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-1979","authenticated-orcid":true,"given":"Kathleen 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