<i>Cis</i>variants identified in F508del complex alleles modulate CFTR channel rescue by small molecules

Baatallah, Nesrine; Bitam, Sara; Martin, Natacha; Servel, Nathalie; Costes, Bruno; Mekki, Chadia; Chevalier, B.; Pranke, Iwona; Simonin, Juliette; Girodon, Emmanuelle; Hoffmann, Brice; Mornon, Jean‐Paul; Callebaut, Isabelle; Sermet‐Gaudelus, Isabelle; Fanen, Pascale; Edelman, Aleksander; Hinzpeter, Alexandre

doi:10.1002/humu.23389

Cited by 29 publications

(45 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For secondary mutations which induced CFTR misfolding (M152W, M156W, H199W/A and I368W), both F508del and L206W correction was prevented (Fig. S3 (D and E)), in this case probably due to additive folding defects, as was previously demonstrated for cis mutation L467F (25). Of note, cis-mutations F87L and L53V which prevented VX-809 correction of F508del CFTR are located in the vicinity of the inner binding site (Fig.…”

Section: Exploring Key Residues Of the Msd1 Vx-809 Binding Pocketssupporting

confidence: 65%

“…We have previously shown that cis mutations of F508del could alter the response to VX-809 treatment, either by inducing an additional folding defect as for L467F (25) or by altering a potential VX-809 binding site as suggested with F87L (26). Here, we evaluated the effect of L53V, another cis mutation located in the N-terminal part of CFTR, called the lasso motif and defined after the first high-resolution experimental 3D structures of zebrafish and human CFTR (27,28).…”

Section: A Potential Vx-809 Binding Site Highlighted Within Msd1 By Molecular Dockingmentioning

confidence: 99%

See 1 more Smart Citation

CFTR corrector efficacy is associated with occupancy of distinct binding sites

Baatallah

Elbahnsi

Mornon

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

CFTR misfolding due to cystic fibrosis causing mutations can be corrected with small molecules designated as correctors. VX-809, an investigational corrector compound, is believed to bind CFTR directly to either the first membrane-spanning domain (MSD1) and/or the first nucleotide-binding domain (NBD1). Blind docking onto the 3D structures of these domains, followed by molecular dynamics (MD) simulations, revealed the presence of two potential VX-809 binding sites which, when mutated, abrogated corrector rescue. Mutations altering protein maturation are also shown to be not equally sensitive to the occupancy of the two sites by VX-809, with the most frequent mutation F508del requiring integrity of both sites and allosteric coupling with the F508del region while L206W only requires the integrity of the MSD1 site. A network of charged amino acids in the lasso Lh2 helix and the intracellular loops ICL1 and ICL4 is involved in the allostery between MSD1 and NBD1. Corrector VX-445, which is used in combination in clinics with VX-661, a structurally close analog of VX-809, to fully correct F508del, is also shown to occupy two potential binding sites on MSD1 and NBD1, the latter being shared with VX-809. In conclusion, VX-809 and VX-445 appear to bind different CFTR domains to alleviate specific folding defects. These results provide new insights into therapeutics understanding and may help the development of efficient corrector combinations.

show abstract

Section: Exploring Key Residues Of the Msd1 Vx-809 Binding Pocketssupporting

confidence: 65%

Section: A Potential Vx-809 Binding Site Highlighted Within Msd1 By Molecular Dockingmentioning

confidence: 99%

CFTR corrector efficacy is associated with occupancy of distinct binding sites

Baatallah

Elbahnsi

Mornon

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, the effects of Lumacaftor were neither global nor of equal efficacy for all Class II variants [99], similar to what is seen with Vx770 in the potentiation of class III CF variants. Its use in combination with Vx770, referred to as Orkambi [93, 100–103], to potentiate the channel gating of the cell surface delivered F508del variant, was approved by the FDA for use in patients carrying at least one F508del variant allele in 2015. Taken together, these data highlight the need for a better understanding of the mechanism of action of therapeutics to predict the spectrum of variants for which Lumacaftor and Orkambi will be efficacious for personalized medicine-based approach for ER-restricted class II variants.…”

Section: Resultsmentioning

confidence: 99%

A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease

Hutt

Loguercio

Campos

et al. 2018

Journal of Molecular Biology

View full text Add to dashboard Cite

The advent of precision medicine for genetic diseases has been hampered by the large number of variants that cause familial and somatic disease, a complexity that is further confounded by the impact of genetic modifiers. To begin to understand differences in onset, progression and therapeutic response that exist among disease-causing variants, we present the proteomic variant approach (ProVarA), a proteomic method that integrates mass spectrometry with genomic tools to dissect the etiology of disease. To illustrate its value, we examined the impact of variation in cystic fibrosis (CF), where 2025 disease-associated mutations in the CF transmembrane conductance regulator (CFTR) gene have been annotated and where individual genotypes exhibit phenotypic heterogeneity and response to therapeutic intervention. A comparative analysis of variant-specific proteomics allows us to identify a number of protein interactions contributing to the basic defects associated with F508del- and G551D-CFTR, two of the most common disease-associated variants in the patient population. We demonstrate that a number of these causal interactions are significantly altered in response to treatment with Vx809 and Vx770, small-molecule therapeutics that respectively target the F508del and G551D variants. ProVarA represents the first comparative proteomic analysis among multiple disease-causing mutations, thereby providing a methodological approach that provides a significant advancement to existing proteomic efforts in understanding the impact of variation in CF disease. We posit that the implementation of ProVarA for any familial or somatic mutation will provide a substantial increase in the knowledge base needed to implement a precision medicine-based approach for clinical management of disease.

show abstract

“…The variant L467F, found in cis with F508del in patient two, is a rare variant (exact frequency 0.00005%) first identified in France (and reported in CF Mutation Database). It was identified in one case out of 56 in a study of children with CF from North‐West of Iran .…”

Section: Lessons Learnedmentioning

confidence: 88%

Should isolated Pseudo‐Bartter syndrome be considered a CFTR‐related disorder of infancy?

Poli

Rose

Timpano

et al. 2019

Pediatric Pulmonology

View full text Add to dashboard Cite

Background Infants that are negative to cystic fibrosis (CF) newborn screening (NBS) programs, or in countries without NBS, may present with metabolic alkalosis and severe salt depletion, a well‐known clinical manifestation of CF termed Pseudo‐Bartter syndrome (PBS). Here, we report the cases of three CF‐negative children, who carry rare mutations in the CF transmembrane conductance regulator (CFTR) gene, and, for whom, PBS was the only manifestation of CFTR protein dysfunction. There is no diagnostic label for these cases. Methods Medical records of patients followed at our Cystic Fibrosis Centre were revised and data were collected for all patients who presented with an isolated PBS. The syndrome was defined as an episode of dehydration with low levels of serum sodium (<134mmol/L), potassium ( <3.4mmol/L), and chloride ( <100mmol/L), with metabolic alkalosis (bicarbonatemia >27mmol/L) in the absence of renal tubulopathy. Results Three out of 73 (4%) CF infants presented with a severe metabolic alkalosis with salt depletion; two of these required admission to the intensive care unit. Two infants had a negative NBS, and one was identified as a CF carrier. Sweat test was repeatedly in the negative/borderline ranges for all patients. Less than two CF causing mutations were identified (F508del/R1070W, F508del; L467F/P5L, R1066H/P5L). During a mean follow‐up of 9 years, the children had no other CF manifestations. Conclusion We suggest that PBS as the sole manifestation of CFTR dysfunction might be considered a CFTR‐related disorder of infancy.

show abstract

Cisvariants identified in F508del complex alleles modulate CFTR channel rescue by small molecules

Cited by 29 publications

References 35 publications

CFTR corrector efficacy is associated with occupancy of distinct binding sites

CFTR corrector efficacy is associated with occupancy of distinct binding sites

A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease

Should isolated Pseudo‐Bartter syndrome be considered a CFTR‐related disorder of infancy?

Contact Info

Product

Resources

About