Details

Autor(en) / Beteiligte

• Sharma, Neeraj
• Evans, Taylor A
• Pellicore, Matthew J
• Davis, Emily
• Aksit, Melis A
• McCague, Allison F
• Joynt, Anya T
• Lu, Zhongzhu
• Han, Sangwoo T
• Anzmann, Arianna F
• Lam, Anh-Thu N
• Thaxton, Abigail
• West, Natalie
• Merlo, Christian
• Gottschalk, Laura B
• Raraigh, Karen S
• Sosnay, Patrick R
• Cotton, Calvin U
• Cutting, Garry R
• Barsh, Gregory S.

Titel

Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis

Ist Teil von

• PLoS genetics, 2018-11, Vol.14 (11), p.e1007723-e1007723

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2018

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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)) and Group B (normal mRNA, immature protein, function <1% (n = 10)) variants were unresponsive to modulator treatment. However, Group C (normal mRNA, mature (fully 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.