CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) 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 ivacaf...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-03-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.148841 |
| _version_ | 1811238000322936832 |
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| author | Karen S. Raraigh Kathleen C. Paul Jennifer L. Goralski Erin N. Worthington Anna V. Faino Stanley Sciortino Yiting Wang Melis A. Aksit Hua Ling Derek L. Osorio Frankline M. Onchiri Shivani U. Patel Christian A. Merlo Kristina Montemayor Ronald L. Gibson Natalie E. West Amita Thakerar Robert J. Bridges David N. Sheppard Neeraj Sharma Garry R. Cutting |
| author_facet | Karen S. Raraigh Kathleen C. Paul Jennifer L. Goralski Erin N. Worthington Anna V. Faino Stanley Sciortino Yiting Wang Melis A. Aksit Hua Ling Derek L. Osorio Frankline M. Onchiri Shivani U. Patel Christian A. Merlo Kristina Montemayor Ronald L. Gibson Natalie E. West Amita Thakerar Robert J. Bridges David N. Sheppard Neeraj Sharma Garry R. Cutting |
| author_sort | Karen S. Raraigh |
| collection | DOAJ |
| description | The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) 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–]; 87–105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl–] (75–123 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% ± 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–) cells, F312del-CFTR demonstrated residual function (50.9% ± 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. |
| first_indexed | 2024-04-12T12:34:13Z |
| format | Article |
| id | doaj.art-78b4738b6909425d927439919d715df3 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T12:34:13Z |
| publishDate | 2022-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-78b4738b6909425d927439919d715df32022-12-22T03:32:57ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-03-0176CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftorKaren S. RaraighKathleen C. PaulJennifer L. GoralskiErin N. WorthingtonAnna V. FainoStanley SciortinoYiting WangMelis A. AksitHua LingDerek L. OsorioFrankline M. OnchiriShivani U. PatelChristian A. MerloKristina MontemayorRonald L. GibsonNatalie E. WestAmita ThakerarRobert J. BridgesDavid N. SheppardNeeraj SharmaGarry R. CuttingThe chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) 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–]; 87–105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl–] (75–123 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% ± 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–) cells, F312del-CFTR demonstrated residual function (50.9% ± 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.https://doi.org/10.1172/jci.insight.148841Genetics |
| spellingShingle | Karen S. Raraigh Kathleen C. Paul Jennifer L. Goralski Erin N. Worthington Anna V. Faino Stanley Sciortino Yiting Wang Melis A. Aksit Hua Ling Derek L. Osorio Frankline M. Onchiri Shivani U. Patel Christian A. Merlo Kristina Montemayor Ronald L. Gibson Natalie E. West Amita Thakerar Robert J. Bridges David N. Sheppard Neeraj Sharma Garry R. Cutting CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor JCI Insight Genetics |
| title | CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor |
| title_full | CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor |
| title_fullStr | CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor |
| title_full_unstemmed | CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor |
| title_short | CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor |
| title_sort | cftr bearing variant p phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor |
| topic | Genetics |
| url | https://doi.org/10.1172/jci.insight.148841 |
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