N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

Gené, Gemma G.; Llobet, A.; Larriba, Sara; Semir, David de; Martı́nez, Iciar; Escalada, Alvaro; Solsona, Carles; Casals, Teresa; Aran, Josep M.

doi:10.1002/humu.20721

Cited by 28 publications

(24 citation statements)

References 63 publications

(60 reference statements)

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“…The c.224G > A variant is polymorphic at amino acid level, but appears to have channel activity not different from the wild-type CFTR. 29 The c.224A allele was found to be significantly more frequent in patients with mild pulmonary manifestations, such as atypical cystic fibrosis. 30 The increased frequency of this variant was also observed in Serbian patients with chronic obstructive pulmonary disease.…”

Section: Discussionmentioning

confidence: 99%

Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children

Milošević

Nikolić²,

Rankov³

et al. 2013

Pediatric Allergy, Immunology, and Pulmonology

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Section: Discussionmentioning

confidence: 99%

Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children

Milošević

Nikolić²,

Rankov³

et al. 2013

Pediatric Allergy, Immunology, and Pulmonology

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“…The S13F mutation is one of several mutations in the CFTR N terminus that are listed in the Cystic Fibrosis Mutation Database. Two other mutations in this region, P5L and W19C, are thought to cause CF primarily because they lead to biosynthetic defects (53). In titrations of 15 N-FlnA-Ig21 with CFTR N-terminal peptides containing these mutations, the P5L interacted robustly with the Ig repeat whereas W19C interacted more weakly (data not shown).…”

Section: Filamin Ig Repeat Interactions With Cftrmentioning

confidence: 96%

Biochemical Basis of the Interaction between Cystic Fibrosis Transmembrane Conductance Regulator and Immunoglobulin-like Repeats of Filamin

Smith

Page

et al. 2010

Journal of Biological Chemistry

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Mutations in the chloride channel cystic fibrosis transmembrane regulator (CFTR) cause cystic fibrosis, a genetic disorder characterized by defects in CFTR biosynthesis, localization to the cell surface, or activation by regulatory factors. It was discovered recently that surface localization of CFTR is stabilized by an interaction between the CFTR N terminus and the multidomain cytoskeletal protein filamin. The details of the CFTRfilamin interaction, however, are unclear. Using x-ray crystallography, we show how the CFTR N terminus binds to immunoglobulin-like repeat 21 of filamin A (FlnA-Ig21). CFTR binds to ␤-strands C and D of FlnA-Ig21 using backbone-backbone hydrogen bonds, a linchpin serine residue, and hydrophobic side-chain packing. We use NMR to determine that the CFTR N terminus also binds to several other immunoglobulinlike repeats from filamin A in vitro. Our structural data explain why the cystic fibrosis-causing S13F mutation disrupts CFTRfilamin interaction. We show that FlnA-Ig repeats transfected into cultured Calu-3 cells disrupt CFTR-filamin interaction and reduce surface levels of CFTR. Our findings suggest that filamin A stabilizes surface CFTR by anchoring it to the actin cytoskeleton through interactions with multiple filamin Ig repeats. Such an interaction mode may allow filamins to cluster multiple CFTR molecules and to promote colocalization of CFTR and other filamin-binding proteins in the apical plasma membrane of epithelial cells.Cystic fibrosis (CF) 4 is a genetic disorder caused by mutations in an apical chloride channel, cystic fibrosis transmembrane regulator (CFTR). This disorder is characterized by high sweat chloride concentration, pulmonary disease with high production of dehydrated viscous secretions, and pancreatic insufficiency (1). CF affects all exocrine epithelia, with morbidity and mortality primarily caused by bacterial infection and inflammation in the lung. CF affects ϳ30,000 individuals in North America, of whom about 70% carry one copy of the mutation ⌬F508, the most common of Ͼ1,000 CF-associated mutations. ⌬F508 is a folding mutation that leads to rapid degradation at the endoplasmic reticulum. The small fraction of ⌬F508-CFTR that is not degraded is characterized by inefficient trafficking to the apical plasma membrane and reduced residency in the plasma membrane (2, 3).Although the levels of ⌬F508-CFTR in the apical plasma membrane are low, ⌬F508-CFTR retains partial function as a cAMP-activated chloride channel (4, 5). This justifies therapeutic approaches to promote delivery of ⌬F508-CFTR and other functionally impaired CFTR mutants to the plasma membrane. A detailed understanding of factors that stabilize and regulate CFTR at the plasma membrane is important for the development of new therapies to correct CF-causing defects in vivo.CFTR is regulated by intracellular cAMP levels and phosphorylated at multiple sites by cAMP-activated protein kinase, which modulates CFTR trafficking (6) and activity (7,8). We and others have identified and characterized addit...

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“…The P5L mutation consists an N-terminus CFTR missense variant which has been recently described in Spain [7]. Eight different N-terminus missense natural variants have been detected which cause a defect of CFTR folding and or/trafficking, thus severely affecting the chloride channel activity.…”

Section: Introductionmentioning

confidence: 99%

Mild cystic fibrosis in patients with the rare P5L CFTR mutation

Spicuzza

Sciuto

Dio

et al. 2012

Journal of Cystic Fibrosis

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Over 1800 Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) mutations have been identified so far, determining different degrees of CFTR dysfunction and a range of different cystic fibrosis phenotypes. The P5L CFTR mutation is a recently described N-terminus missense variant which may cause defect of protein folding and processing/trafficking, but the functional classification is still unclear. Given the rarity of the mutation, the associated clinical phenotype is still unknown. The aim of our study was to describe the clinical phenotypes in a group of 7 patients with the P5L mutation including 2 adults, 2 adolescents and 3 children. The P5L variant was associated with ΔF508 in 5 patients and with W1282X in two patients. All patients had positive or borderline sweat test values. All had pancreatic sufficiency, no hepatobiliary disease, no or mild respiratory symptoms and normal lung function. The two adult males were fertile. Most of the patients presented recurrent episodes of dehydration and hypochloronatremia. We conclude that, although it has been speculated that the N-terminus CFTR missense variants may severely affect the behaviour of the CFTR chloride channel, patients with the P5L CFTR mutation, in association with a severe class II mutation, may be asymptomatic or may be affected by mild disease.

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N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel

Cited by 28 publications

References 63 publications

Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children

Analysis of CFTR Gene Variants in Idiopathic Bronchiectasis in Serbian Children

Biochemical Basis of the Interaction between Cystic Fibrosis Transmembrane Conductance Regulator and Immunoglobulin-like Repeats of Filamin

Mild cystic fibrosis in patients with the rare P5L CFTR mutation

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