Academic Journal
Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.
| Title: | Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis. |
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| Authors: | Neeraj Sharma, Taylor A Evans, Matthew J Pellicore, Emily Davis, Melis A Aksit, Allison F McCague, Anya T Joynt, Zhongzhu Lu, Sangwoo T Han, Arianna F Anzmann, Anh-Thu N Lam, Abigail Thaxton, Natalie West, Christian Merlo, Laura B Gottschalk, Karen S Raraigh, Patrick R Sosnay, Calvin U Cotton, Garry R Cutting |
| Source: | PLoS Genetics, Vol 14, Iss 11, p e1007723 (2018) |
| Publisher Information: | Public Library of Science (PLoS), 2018. |
| Publication Year: | 2018 |
| Collection: | LCC:Genetics |
| Subject Terms: | Genetics, QH426-470 |
| More Details: | CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function 1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic 'nulls' as some may allow generation of protein that can be targeted to achieve clinical benefit. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1553-7390 1553-7404 |
| Relation: | https://doaj.org/toc/1553-7390; https://doaj.org/toc/1553-7404 |
| DOI: | 10.1371/journal.pgen.1007723 |
| Access URL: | https://doaj.org/article/c0c6949dd9f04b7d817e9247c8d75a77 |
| Accession Number: | edsdoj.0c6949dd9f04b7d817e9247c8d75a77 |
| Database: | Directory of Open Access Journals |
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| ISSN: | 15537390 15537404 |
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| DOI: | 10.1371/journal.pgen.1007723 |
| Published in: | PLoS Genetics |
| Language: | English |