Frequency and phenotypic consequences of the 3199del6 CFTR mutation in French Canadians

The rare Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, c.1826A > G (H609R) and c.3067_3072delATAGTG (I1023_V1024del), are associated with severe lung disease. Despite the existence of four CFTR targeted therapies, none have been approved for individuals with these mutations because the associated molecular defects were not known. In this study we examined the consequences of these mutations on protein processing and channel function in HEK293 cells. We found that, similar to F508del, H609R and I1023_V1024del-CFTR exhibited reduced protein processing and altered channel function. Because the I1023_V1024del mutation can be linked with the mutation, I148T, we also examined the protein conferred by transfection of a plasmid bearing both mutations. Interestingly, together with I148T, there was no further reduction in channel function exhibited by I1023-V1024del. Both H609R and I1023_V1024del failed to exhibit significant correction of their functional expression with lumacaftor and ivacaftor. In contrast, the triple modulator combination found in TRIKAFTATM, i.e., tezacaftor, elexacaftor and ivacaftor rescued trafficking and function of both of these mutants. These in-vitro findings suggest that patients harbouring H609R or I1023_V1024del, alone or with I148T, may benefit clinically from treatment with TRIKAFTATM.

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Phenotyping Rare CFTR Mutations Reveal Functional Expression Defects Restored by TRIKAFTATM

Laselva

Ardelean

Bear

2021

JPM

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Effect of the Complex Allele p.[Ile148Thr;Ile1023_Val1024del] in Cystic Fibrosis and Tracing of a Founder Effect in Mexican Families

Mendiola-Vidal,

Contreras-Cubas,

Barajas-Olmos

et al. 2024

Life

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Cystic fibrosis (CF) is a rare autosomal recessive disease most commonly affecting the Caucasian population. CF diagnosis can be a challenge due to the large spectrum of pathogenic variants in the CFTR gene and the effects of complex alleles. Next-generation sequencing has improved our understanding of the contribution of these complex alleles to the wide spectrum of CF clinical symptoms and to the response to medications. Herein, we studied nine CF patients from six unrelated families carrying the complex allele p.[Ile148Thr;Ile1023_Val1024del] with a frequency of 0.18%. All patients were from Central Mexico. This complex allele was found in trans with Class I and II pathogenic variants such as p.(Phe508del), and p.(Phe1078Profs*77)]. A targeted search of a dataset of 2217 exomes from healthy individuals revealed that eight individuals (0.18%) carried the p.(Ile148Thr) variant, but only one (0.022%), who was also born in Central Mexico, was a carrier of the complex allele. These findings show an enrichment of this p.[Ile148Thr;Ile1023_Val1024del] complex allele in Mexican CF patients in this region of Mexico. Finally, protein modeling revealed that this complex allele disrupts the secondary structure of the CFTR protein and might alter the ion flow.

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Frequency and phenotypic consequences of the 3199del6 CFTR mutation in French Canadians

Cited by 2 publications

References 10 publications

Phenotyping Rare CFTR Mutations Reveal Functional Expression Defects Restored by TRIKAFTATM

Phenotyping Rare CFTR Mutations Reveal Functional Expression Defects Restored by TRIKAFTATM

Effect of the Complex Allele p.[Ile148Thr;Ile1023_Val1024del] in Cystic Fibrosis and Tracing of a Founder Effect in Mexican Families

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