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Fortunately, a triple-modulator combination therapy (Trikafta) has been FDA-approved for 178 mutations, including all patients who have F508del on one allele. That so many CFTR mutants respond well to modulators developed for a single mutation is due to the nature of the folding process of this multidomain protein. We have addressed the question \u2018What characterizes the exceptions: the mutants that functionally respond either not or extremely well\u2019. A functional response is the product of the number of CFTR molecules on the cell surface, open probability, and conductivity of the CFTR chloride channel. By combining biosynthetic radiolabeling with protease-susceptibility assays, we have followed CF-causing mutants during the early and late stages of folding in the presence and absence of modulators. Most CFTR mutants showed typical biochemical responses for each modulator, such as a TMD1 conformational change or an increase in (cell-surface) stability, regardless of a functional response. These modulators thus should still be considered for hypo-responder genotypes. Understanding both biochemical and functional phenotypes of outlier mutations will boost our insights into CFTR folding and misfolding, and lead to improved therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms232315170","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T03:55:37Z","timestamp":1669953337000},"page":"15170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0672-2947","authenticated-orcid":false,"given":"Tamara","family":"Hillenaar","sequence":"first","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Science for Life, Faculty of Science, Utrecht University, 3584 CS Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Beekman","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht, Utrecht University, Member of ERN-LUNG, 3584 EA Utrecht, The Netherlands"},{"name":"Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands"},{"name":"Centre for Living Technologies, Alliance TU\/e, WUR, UU, UMC Utrecht, 3584 CB Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"van der Sluijs","sequence":"additional","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Science for Life, Faculty of Science, Utrecht University, 3584 CS Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-4364","authenticated-orcid":false,"given":"Ineke","family":"Braakman","sequence":"additional","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Science for Life, Faculty of Science, Utrecht University, 3584 CS Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cell.2017.02.024","article-title":"Molecular Structure of the Human CFTR Ion Channel","volume":"169","author":"Liu","year":"2017","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12757","DOI":"10.1073\/pnas.1815287115","article-title":"Molecular structure of the ATP-bound, phosphorylated human CFTR","volume":"115","author":"Zhang","year":"2018","journal-title":"Proc. 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