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

被引:38
作者
Amato, Felice [1 ]
Scudieri, Paolo [2 ]
Musante, Ilaria [2 ]
Tomati, Valeria [3 ]
Caci, Emanuela [3 ]
Comegna, Marika [1 ]
Maietta, Sabrina [1 ]
Manzoni, Francesca [1 ]
Di Lullo, Antonella Miriam [1 ]
De Wachter, Elke [4 ]
Vanderhelst, Eef [4 ]
Terlizzi, Vito [5 ]
Braggion, Cesare [5 ]
Castaldo, Giuseppe [1 ]
Galietta, Luis J., V [2 ,6 ]
机构
[1] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, CEINGE Biotecnol Avanzate, Naples, Italy
[2] Telethon Inst Genet & Med TIGEM, Cell Biol & Dis Mech Program, Pozzuoli, Italy
[3] Ist Giannina Gaslini, UOC Genet Med, Genoa, Italy
[4] Vrije Univ Brussel, Univ Ziekenhuis Brussel, CF Ctr, Brussels, Belgium
[5] Azienda Osped Univ Meyer, Ctr Regionale Toscano Fibrosi Cist, Florence, Italy
[6] Univ Naples Federico II, Dept Translat Med Sci DISMET, Naples, Italy
关键词
airway epithelium; CFTR; chloride channel; cystic fibrosis; RNA splicing; CYSTIC-FIBROSIS; IN-VITRO; POTENTIATOR; CORRECTORS; DELTA-F508; THERAPIES; MECHANISM; RESCUE;
D O I
10.1002/humu.23741
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:742 / 748
页数:7
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