Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies

Fanen, Pascale; Wohlhuter-Haddad, Adeline; Hinzpeter, Alexandre

doi:10.1016/j.biocel.2014.02.023

Cited by 83 publications

(69 citation statements)

References 75 publications

(72 reference statements)

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“…35 Examples of genes with variants that principally affect protein abundance include tumor suppressors (e.g., TP53 [MIM: 191170]) and genes that underlie Mendelian diseases (e.g., CFTR [MIM: 602421]). [35][36][37] A yeast metabolic reporter fusion assay for variant stability has already been developed. 38 A similar assay could be developed in human cells.…”

Section: Annotating Every Possible Variant In Disease-related Functiomentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

293

294

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Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of ''lookup tables'' of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.

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Section: Annotating Every Possible Variant In Disease-related Functiomentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

293

294

View full text Add to dashboard Cite

show abstract

“…So far, a large number of CF-causing mutations have been identified. CF mutations are classified in 5 classes according to the mechanism of CFTR loss-of-function [2]. The most common genetic defect, occurring in 70e90% of CF patients, is the deletion of phenylalanine 508 (F508del), located in NBD1.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and structure–activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis

Pesce

Bellotti

Liessi

et al. 2015

European Journal of Medicinal Chemistry

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“…More than 1,900 different CFTR mutations have been identified to cause CF (6). These mutations can be divided into different classes according to the mechanism by which they disrupt CFTR expression (7).…”

mentioning

confidence: 99%

Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR

Stevers

Lam

Leysen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

140

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Cystic fibrosis is a fatal genetic disease, most frequently caused by the retention of the CFTR (cystic fibrosis transmembrane conductance regulator) mutant protein in the endoplasmic reticulum (ER). The binding of the 14-3-3 protein to the CFTR regulatory (R) domain has been found to enhance CFTR trafficking to the plasma membrane. To define the mechanism of action of this protein–protein interaction, we have examined the interaction in vitro. The disordered multiphosphorylated R domain contains nine different 14-3-3 binding motifs. Furthermore, the 14-3-3 protein forms a dimer containing two amphipathic grooves that can potentially bind these phosphorylated motifs. This results in a number of possible binding mechanisms between these two proteins. Using multiple biochemical assays and crystal structures, we show that the interaction between them is governed by two binding sites: The key binding site of CFTR (pS768) occupies one groove of the 14-3-3 dimer, and a weaker, secondary binding site occupies the other binding groove. We show that fusicoccin-A, a natural-product tool compound used in studies of 14-3-3 biology, can stabilize the interaction between 14-3-3 and CFTR by selectively interacting with a secondary binding motif of CFTR (pS753). The stabilization of this interaction stimulates the trafficking of mutant CFTR to the plasma membrane. This definition of the druggability of the 14-3-3–CFTR interface might offer an approach for cystic fibrosis therapeutics.

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Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies

Cited by 83 publications

References 75 publications

Variant Interpretation: Functional Assays to the Rescue

Variant Interpretation: Functional Assays to the Rescue

Synthesis and structure–activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis

Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR

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