Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A>G

For most of the >2000 CFTR gene variants reported, neither the associated disease liability nor the underlying basic defect are known, and yet these are essential for disease prognosis and CFTR-based therapeutics. Here we aimed to characterize two ultra-rare mutations - 1717-2A > G (c.1585-2A ...

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Published in:Biochimica et biophysica acta. Molecular basis of disease 2020-11, Vol.1866 (11), p.165905-165905, Article 165905
Main Authors: Silva, Iris A.L., Doušová, Tereza, Ramalho, Sofia, Centeio, Raquel, Clarke, Luka A., Railean, Violeta, Botelho, Hugo M., Holubová, Andrea, Valášková, Iveta, Yeh, Jiunn-Tyng, Hwang, Tzyh-Chang, Farinha, Carlos M., Kunzelmann, Karl, Amaral, Margarida D.
Format: Article
Language:English
Subjects:
Alleles
Aminophenols - therapeutic use
Aminopyridines - therapeutic use
Benzodioxoles - therapeutic use
Blotting, Western
CFTR modulators
Cystic Fibrosis - drug therapy
Cystic Fibrosis - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Electrophysiology
Fluorescent Antibody Technique
Genotype
Humans
Indoles - therapeutic use
Intestinal organoids
Mutation - genetics
Precision medicine
Precision Medicine - methods
Quinolones - therapeutic use
Rare mutations
Theranostics
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Summary:For most of the >2000 CFTR gene variants reported, neither the associated disease liability nor the underlying basic defect are known, and yet these are essential for disease prognosis and CFTR-based therapeutics. Here we aimed to characterize two ultra-rare mutations - 1717-2A > G (c.1585-2A > G) and S955P (p.Ser955Pro) - as case studies for personalized medicine. Patient-derived rectal biopsies and intestinal organoids from two individuals with each of these mutations and F508del (p.Phe508del) in the other allele were used to assess CFTR function, response to modulators and RNA splicing pattern. In parallel, we used cellular models to further characterize S955P independently of F508del and to assess its response to CFTR modulators. Results in both rectal biopsies and intestinal organoids from both patients evidence residual CFTR function. Further characterization shows that 1717-2A > G leads to alternative splicing generating  G causes alternative splicing generating
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2020.165905