{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T22:25:24Z","timestamp":1778797524863,"version":"3.51.4"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["GNT1188987"],"award-info":[{"award-number":["GNT1188987"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Cystic fibrosis (CF) is caused by a wide spectrum of mutations in the CF transmembrane conductance regulator (<jats:italic>CFTR<\/jats:italic>) gene, with some leading to non-classical clinical presentations. We present an integrated <jats:italic>in vivo, in silico<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> investigation of an individual with CF carrying the rare Q1291H<jats:italic>-CFTR<\/jats:italic> allele and the common F508del allele. At age 56\u00a0years, the participant had obstructive lung disease and bronchiectasis, qualifying for Elexacaftor\/Tezacaftor\/Ivacaftor (ETI) CFTR modulator treatment due to their F508del allele. Q1291H <jats:italic>CFTR<\/jats:italic> incurs a splicing defect, producing both a normally spliced but mutant mRNA isoform and a misspliced isoform with a premature termination codon, causing nonsense mediated decay. The effectiveness of ETI in restoring Q1291H-CFTR is largely unknown.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We collected clinical endpoint measurements, including forced expiratory volume in 1\u00a0s percent predicted (FEV1pp) and body mass index (BMI), and examined medical history. <jats:italic>In silico<\/jats:italic> simulations of the Q1291H-CFTR were compared to Q1291R, G551D, and wild-type (WT)-CFTR. We quantified relative Q1291H <jats:italic>CFTR<\/jats:italic> mRNA isoform abundance in patient-derived nasal epithelial cells. Differentiated pseudostratified airway epithelial cell models at air liquid interface were created and ETI treatment impact on CFTR was assessed by electrophysiology assays and Western blot.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The participant ceased ETI treatment after 3\u00a0months due to adverse events and no improvement in FEV1pp or BMI. <jats:italic>In silico<\/jats:italic> simulations of Q1291H-CFTR identified impairment of ATP binding similar to known gating mutants Q1291R and G551D-CFTR. Q1291H and F508del mRNA transcripts composed 32.91% and 67.09% of total mRNA respectively, indicating 50.94% of Q1291H mRNA was misspliced and degraded. Mature Q1291H-CFTR protein expression was reduced (3.18% \u00b1 0.60% of WT\/WT) and remained unchanged with ETI. Baseline CFTR activity was minimal (3.45 \u00b1 0.25\u00a0\u03bcA\/cm<jats:sup>2<\/jats:sup>) and not enhanced with ETI (5.73 \u00b1 0.48\u00a0\u03bcA\/cm<jats:sup>2<\/jats:sup>), aligning with the individual\u2019s clinical evaluation as a non-responder to ETI.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The combination of <jats:italic>in silico<\/jats:italic> simulations and <jats:italic>in vitro<\/jats:italic> theratyping in patient-derived cell models can effectively assess CFTR modulator efficacy for individuals with non-classical CF manifestations or rare <jats:italic>CFTR<\/jats:italic> mutations, guiding personalized treatment strategies and optimizing clinical outcomes.<\/jats:p>","DOI":"10.3389\/fmolb.2023.1148501","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T04:42:25Z","timestamp":1685594545000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Q1291H-CFTR molecular dynamics simulations and ex vivo theratyping in nasal epithelial models and clinical response to elexacaftor\/tezacaftor\/ivacaftor in a Q1291H\/F508del patient"],"prefix":"10.3389","volume":"10","author":[{"given":"Katelin M.","family":"Allan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miro A.","family":"Astore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egi","family":"Kardia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon L.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura K.","family":"Fawcett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Bell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Visser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po-Chia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renate","family":"Griffith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Jaffe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheila","family":"Sivam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orazio","family":"Vittorio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serdar","family":"Kuyucak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shafagh A.","family":"Waters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1062766","DOI":"10.3389\/fped.2022.1062766","article-title":"S945l-Cftr molecular dynamics, functional characterization and tezacaftor\/ivacaftor efficacy in vivo and in vitro in matched pediatric patient-derived cell models","volume":"10","author":"Allan","year":"2022","journal-title":"Front. 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