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Two CFTR mutations within codon 970 differently impact on the chloride channel functionality
Author(s) -
Amato Felice,
Scudieri Paolo,
Musante Ilaria,
Tomati Valeria,
Caci Emanuela,
Comegna Marika,
Maietta Sabrina,
Manzoni Francesca,
Di Lullo Antonella Miriam,
Wachter Elke,
Vanderhelst Eef,
Terlizzi Vito,
Braggion Cesare,
Castaldo Giuseppe,
Galietta Luis J. V.
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23741
Subject(s) - cystic fibrosis transmembrane conductance regulator , biology , rna splicing , cystic fibrosis , mutation , chloride channel , missense mutation , potentiator , mutant , messenger rna , ivacaftor , microbiology and biotechnology , rna , genetics , gene
Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By complementary DNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of messenger RNA (mRNA) from patient's cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level to determine if the pharmacotherapy of CFTR basic defect is appropriate.