High Frequency of CF Transmembrane Conductance Regulator (CFTR) Mutations in a Population with Persistent Asthma and/or Chronic Rhinosinusitis

2009 ◽  
Vol 123 (2) ◽  
pp. S159-S159 ◽  
Author(s):  
M.J. Meth ◽  
M. Serota ◽  
D.W. Rosenthal ◽  
M.T. Santiago ◽  
M.A. Cavuoto
Keyword(s):  
Chronic Rhinosinusitis ◽  
High Frequency ◽  
Persistent Asthma ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cftr Mutations ◽  
Cf Transmembrane Conductance Regulator

scholarly journals Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770

2016 ◽  
Vol 311 (3) ◽  
pp. L550-L559 ◽  
Author(s):  
Martina Gentzsch ◽  
Hong Y. Ren ◽  
Scott A. Houck ◽  
Nancy L. Quinney ◽  
Deborah M. Cholon ◽  
...  
Keyword(s):  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ion Conductance ◽  
Bronchial Epithelial ◽  
Rare Mutation ◽  
Limited Success ◽  
Folding Defect ◽  
Cftr Mutations ◽  
Cf Transmembrane Conductance Regulator ◽  
And Function

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.

Liquid secretion inhibitors reduce mucociliary transport in glandular airways

2002 ◽  
Vol 283 (2) ◽  
pp. L329-L335 ◽  
Author(s):  
Stephen T. Ballard ◽  
Laura Trout ◽  
Anil Mehta ◽  
Sarah K. Inglis
Keyword(s):  
Beat Frequency ◽  
Anion Channel ◽  
Ciliary Beat Frequency ◽  
Mucociliary Transport ◽  
Transmembrane Conductance Regulator ◽  
Inhibitory Effects ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Liquid Absorption ◽  
Cf Transmembrane Conductance Regulator

Because of its possible importance in cystic fibrosis (CF) pulmonary pathogenesis, the effect of anion and liquid secretion inhibitors on airway mucociliary transport was examined. When excised porcine tracheas were treated with ACh to induce gland liquid secretion, the rate of mucociliary transport was increased nearly threefold from 2.5 ± 0.5 to 6.8 ± 0.8 mm/min. Pretreatment with both bumetanide and dimethylamiloride (DMA), to respectively inhibit Cl− and HCO[Formula: see text]secretion, significantly reduced mucociliary transport in the presence of ACh by 92%. Pretreatment with the anion channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid similarly reduced mucociliary transport in ACh-treated airways by 97%. These agents did not, however, reduce ciliary beat frequency. Luminal application of benzamil to block liquid absorption significantly attenuated the inhibitory effects of bumetanide and DMA on mucociliary transport. We conclude that anion and liquid secretion is essential for normal mucociliary transport in glandular airways. Because the CF transmembrane conductance regulator protein likely mediates Cl−, HCO[Formula: see text], and liquid secretion in normal glands, we speculate that impairment of gland liquid secretion significantly contributes to defective mucociliary transport in CF.

scholarly journals Outcomes of early repeat sweat testing in infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID)

2021 ◽  
Author(s):  
vito terlizzi ◽  
Laura Claut ◽  
Carla Colombo ◽  
Antonella Tosco ◽  
Alice Castaldo ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Definitive Diagnosis ◽  
First Year ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Sweat Chloride ◽  
Sweat Testing ◽  
Cf Transmembrane Conductance Regulator ◽  
First Year Of Life

Background: Reaching early and definitive diagnosis in infants with cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID) is a priority of all CF newborn screening programs. Currently, sweat testing is the gold standard for CF diagnosis or exclusion. We assessed outcomes in a cohort of Italian CRMS/CFSPID infants who underwent repeat sweat testing in the first year of life. Methods: This multicentre, prospective study analysed clinical data and outcomes in CRMS/CFSPID infants born between September 1, 2018 and December 31, 2019, and followed until June 30, 2020. All subjects underwent CF transmembrane conductance regulator (CFTR) gene sequencing and the search for CFTR macrodeletions/macroduplications, and repeat sweat testing in the first year of life. Results: Fifty subjects (median age at end of follow-up, 16 months [range, 7–21 months]) were enrolled. Forty-one (82%) had the first sweat chloride in the intermediate range. During follow up, 150 sweat tests were performed (range, 1–7/infant). After a median follow-up of 8.5 months (range 1–16.2 months), 11 (22%) subjects were definitively diagnosed as follows: CF (n=2 [4%]) at 2 and 5 months, respectively; healthy carrier (n=8 [16%]), at a median age of 4 months (range 2–8 months); and healthy (n=1 [2%]) at 2 months of age. Inconclusive diagnosis remained in 39 (78%) infants. Conclusions: Early repeat sweat testing in the first year of life can shorten the time to definitive diagnosis in screening positive subjects with initial sweat chloride levels in the intermediate range.

scholarly journals Preclinical Studies of a Rare CF-Causing Mutation in the Second Nucleotide Binding Domain (c.3700A>G) Show Robust Functional Rescue in Primary Nasal Cultures by Novel CFTR Modulators

2020 ◽  
Vol 10 (4) ◽  
pp. 209
Author(s):  
Onofrio Laselva ◽  
Jacqueline McCormack ◽  
Claire Bartlett ◽  
Wan Ip ◽  
Tarini N. A. Gunawardena ◽  
...  
Keyword(s):  
Hek293 Cells ◽  
Transmembrane Conductance Regulator ◽  
The Novel ◽  
Triple Combination ◽  
Nucleotide Binding Domain ◽  
Transmembrane Conductance ◽  
Rare Mutation ◽  
Cftr Mutations ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

The combination therapies ORKAMBITM and TRIKAFTATM are approved for people who have the F508del mutation on at least one allele. In this study we examine the effects of potentiator and corrector combinations on the rare mutation c.3700A>G. This mutation produces a cryptic splice site that deletes six amino acids in NBD2 (I1234-R1239del). Like F508del it causes protein misprocessing and reduced chloride channel function. We show that a novel cystic fibrosis transmembrane conductance regulator CFTR modulator triple combination (AC1, corrector, AC2-2, co-potentiator and AP2, potentiator), rescued I1234-R1239del-CFTR activity to WT-CFTR level in HEK293 cells. Moreover, we show that although the response to ORKAMBI was modest in nasal epithelial cells from two individuals homozygous for I1234-R1239del-CFTR, a substantial functional rescue was achieved with the novel triple combination. Interestingly, while both the novel CFTR triple combination and TRIKAFTATM treatment showed functional rescue in gene-edited I1234-R1239del-CFTR-expressing HBE cells and in nasal cells from two CF patients heterozygous for I1234-R1239del/W1282X, nasal cells homozygous for I1234-R1239del-CFTR showed no significant response to the TRIKAFTATM combination. These data suggest a potential benefit of CFTR modulators on the functional rescue of I1234-R1239del -CFTR, which arises from the rare CF-causing mutation c.3700A>G, and highlight that patient tissues are crucial to our full understanding of functional rescue in rare CFTR mutations.

High frequency of (TG)mTn variant tracts in the cystic fibrosis transmembrane conductance regulator gene in men with high semen viscosity

2004 ◽  
Vol 82 (5) ◽  
pp. 1316-1322 ◽  
Author(s):  
Tiziana Rossi ◽  
Francesco Grandoni ◽  
Fernando Mazzilli ◽  
Serena Quattrucci ◽  
Mariano Antonelli ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
High Frequency ◽  
Transmembrane Conductance Regulator ◽  
Regulator Gene ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

scholarly journals VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

2013 ◽  
Vol 24 (19) ◽  
pp. 3016-3024 ◽  
Author(s):  
Hong Yu Ren ◽  
Diane E. Grove ◽  
Oxana De La Rosa ◽  
Scott A. Houck ◽  
Pattarawut Sopha ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Genetic Disorder ◽  
Missense Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Folding Defect ◽  
Membrane Spanning ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

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