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Cis variants identified in F508del complex alleles modulate CFTR channel rescue by small molecules
Author(s) -
Baatallah Nesrine,
Bitam Sara,
Martin Natacha,
Servel Nathalie,
Costes Bruno,
Mekki Chadia,
Chevalier Benoit,
Pranke Iwona,
Simonin Juliette,
Girodon Emmanuelle,
Hoffmann Brice,
Mor JeanPaul,
Callebaut Isabelle,
SermetGaudelus Isabelle,
Fanen Pascale,
Edelman Aleksander,
Hinzpeter Alexandre
Publication year - 2018
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.23389
Subject(s) - potentiator , biology , allele , context (archaeology) , mutation , minigene , compound heterozygosity , genetics , exon , gene , alternative splicing , paleontology
Abstract Molecules correcting the trafficking (correctors) and gating defects (potentiators) of the cystic fibrosis causing mutation c.1521_1523delCTT (p.Phe508del) begin to be a useful treatment for CF patients bearing p.Phe508del. This mutation has been identified in different genetic contexts, alone or in combination with variants in cis . Until now, 21 exonic variants in cis of p.Phe508del have been identified, albeit at a low frequency. The aim of this study was to evaluate their impact on the efficacy of CFTR‐directed corrector/potentiator therapy (Orkambi). The analysis by minigene showed that two out of 15 cis variants tested increased exon skipping (c.609C > T and c.2770G > A). Four cis variants were studied functionally in the absence of p.Phe508del, one of which was found to be deleterious for protein maturation c.1399C > T (p.Leu467Phe). In the presence of p.Phe508del, this variant was the only to prevent the response to Orkambi treatment. This study showed that some patients carrying p.Phe508del complex alleles are predicted to poorly respond to corrector/potentiator treatments. Our results underline the importance to validate treatment efficacy in the context of complex alleles.