Phenotypic and molecular characteristics of CF patients carrying the I1234V mutation.
Adolescent
Adult
Aminophenols
/ therapeutic use
Aminopyridines
/ therapeutic use
Benzodioxoles
/ therapeutic use
Computer Simulation
Cystic Fibrosis
/ drug therapy
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Drug Combinations
Female
Homozygote
Humans
Loss of Function Mutation
/ genetics
Male
Middle Aged
Molecular Targeted Therapy
Phenotype
Quinolones
/ therapeutic use
Retrospective Studies
Time Factors
Young Adult
Cystic fibrosis
I1234V CF mutation
Modulator therapy
Structural CFTR models
Journal
Respiratory medicine
ISSN: 1532-3064
Titre abrégé: Respir Med
Pays: England
ID NLM: 8908438
Informations de publication
Date de publication:
Historique:
received:
26
03
2020
revised:
29
04
2020
accepted:
16
05
2020
entrez:
27
8
2020
pubmed:
28
8
2020
medline:
8
6
2021
Statut:
ppublish
Résumé
The Mutation I1234V is a CF causing mutation; however the mechanisms leading to loss of function are not fully understood. In this study, we aimed to characterize phenotypically individuals with the I1234V variant, and to gain a structural point of view of the mutant CFTR using computational studies. We conducted a retrospective descriptive study, reviewing the clinical records of 9 Israeli patients. The study was designed to include patients either homozygous or compound heterozygous for the I1234V mutation. For a comparison we analyzed clinical data of 12 patients homozygous for the F508del mutation. Computer models were constructed for I1234V, 1234-1239del and wild type CFTR. Mean FEV1 was 73.8 ± 21% predicted with an average annual rate of decline of 1%. When compared to patients homozygous for F508del the mean annual values of FEV1% predicted during the 6 years of data collection ranged from 51 to 58 ± 22-30 in the F508del group versus 76-82 ± 14-19 in the I1234V group (p < 0.05). Structural models did not demonstrate noticeable differences between the three simulated constructs. Although the mutation resides in the NBD2, no interference with ATP binding was detected. This study describes phenotypically patients carrying the I1234V mutation. Compared to patients homozygous for F508del, these patients present with more favorable outcome. Structural models show high similarity between the static and dynamics pictures obtained for both the mutated and the WT-CFTR; however this model does not explore the folding process and therefore may strengthen the notion of a misfolding mutation.
Sections du résumé
BACKGROUND
The Mutation I1234V is a CF causing mutation; however the mechanisms leading to loss of function are not fully understood. In this study, we aimed to characterize phenotypically individuals with the I1234V variant, and to gain a structural point of view of the mutant CFTR using computational studies.
METHODS
We conducted a retrospective descriptive study, reviewing the clinical records of 9 Israeli patients. The study was designed to include patients either homozygous or compound heterozygous for the I1234V mutation. For a comparison we analyzed clinical data of 12 patients homozygous for the F508del mutation. Computer models were constructed for I1234V, 1234-1239del and wild type CFTR.
RESULTS
Mean FEV1 was 73.8 ± 21% predicted with an average annual rate of decline of 1%. When compared to patients homozygous for F508del the mean annual values of FEV1% predicted during the 6 years of data collection ranged from 51 to 58 ± 22-30 in the F508del group versus 76-82 ± 14-19 in the I1234V group (p < 0.05). Structural models did not demonstrate noticeable differences between the three simulated constructs. Although the mutation resides in the NBD2, no interference with ATP binding was detected.
DISCUSSION
This study describes phenotypically patients carrying the I1234V mutation. Compared to patients homozygous for F508del, these patients present with more favorable outcome. Structural models show high similarity between the static and dynamics pictures obtained for both the mutated and the WT-CFTR; however this model does not explore the folding process and therefore may strengthen the notion of a misfolding mutation.
Identifiants
pubmed: 32843167
pii: S0954-6111(20)30167-0
doi: 10.1016/j.rmed.2020.106027
pii:
doi:
Substances chimiques
Aminophenols
0
Aminopyridines
0
Benzodioxoles
0
CFTR protein, human
0
Drug Combinations
0
Quinolones
0
lumacaftor, ivacaftor drug combination
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
106027Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.