Two CFTR mutations within codon 970 differently impact on the chloride channel functionality

Felice Amato, Paolo Scudieri, Ilaria Musante, Valeria Tomati, Emanuela Caci, Marika Comegna, Sabrina Maietta, Francesca Manzoni, Antonella Miriam Di Lullo, Elke De Wachter, Eef Vanderhelst, Vito Terlizzi, Cesare Braggion, Giuseppe Castaldo, Luis J V Galietta

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)742-748
Number of pages7
JournalHuman Mutation
Issue number6
Publication statusPublished - Jun 2019


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