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Meredith C Fidler, Jack Beusmans, Paul Panorchan, Frederick Van Goor
Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor...
October 20, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Ziwei Tu, Qu Chen, Jie Ting Zhang, Xiaohua Jiang, Yunfei Xia, Hsiao Chang Chan
While there is an increasing interest in the correlation of cystic fibrosis transmembrane conductance regulator (CFTR) and cancer incidence, the role of CFTR in nasopharyngeal carcinoma (NPC) development remains unknown. In this study, we aimed to explore the prognostic value of CFTR in NPC patients. The expression of CFTR was determined in NPC cell lines and tissues. Statistical analysis was utilized to evaluate the correlation between CFTR expression levels and clinicopathological characteristics and prognosis in 225 cases of NPC patients...
October 19, 2016: Oncotarget
Jeeyeon Kim, Miesha Farahmand, Colleen Dunn, Zoe Davies, Eric Frisbee, Carlos Milla, Jeffrey J Wine
Beta-adrenergically-stimulated sweat rates determined by evaporimetry or by sweat bubble imaging are useful for measuring CFTR function because they provide a near-linear readout across almost the full range of CFTR function. They differentiate cystic fibrosis (CF) subjects from CF carriers and carriers from controls. However, evaporimetry, unlike bubble imaging, appears to be unable to detect improved levels of CFTR function in G551D subjects taking the CFTR modulator ivacaftor. Here, we quantify the sensitivity of evaporimetry and bubble imaging methods for assessing low levels of CFTR-dependent sweat rates...
2016: PloS One
Shyam Ramachandran, Samantha R Osterhaus, Kalpaj R Parekh, Ashley M Jacobi, Mark A Behlke, Paul B McCray
We previously reported that delivery of a microRNA (miR)-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (CF) (ΔF508/ΔF508) airway epithelia partially restored ΔF508-CFTR mediated cAMP-stimulated Cl-conductance. We hypothesized that dissecting this miR-138/SIN3A regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia...
October 18, 2016: Journal of Biological Chemistry
Benjamin T Kopp, Juan Antonio Ortega-García, S Christy Sadreameli, Jack Wellmerling, Estelle Cormet-Boyaka, Rohan Thompson, Sharon McGrath-Morrow, Judith A Groner
Secondhand smoke exposure (SHSe) has multiple adverse effects on lung function and growth, nutrition, and immune function in children; it is increasingly being recognized as an important modifier of disease severity for children with chronic diseases such as cystic fibrosis (CF). This review examines what is known regarding the prevalence of SHSe in CF, with the majority of reviewed studies utilizing parental-reporting of SHSe without an objective biomarker of exposure. A wide range of SHSe is reported in children with CF, but under-reporting is common in studies involving both reported and measured SHSe...
October 12, 2016: International Journal of Environmental Research and Public Health
Mauricio A Salinas-Santander, Elizabeth Bazan-Mendoza, Marisol Espinoza-Ruiz, Rocio Ortiz-Lopez, Adriana Bustamante, Celia N Sanchez-Dominguez
Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population, but it has also been widely diagnosed in the Mexican population. Production of viscous secretions affects the secretory epithelia and the respiratory condition usually leads to death. The relationship between the CFTR genotype and the disease phenotype is not well understood. Other risk factors such as genetic and autoimmune influence the development of this disease. We analyzed the PTPN22 R620W polymorphism (+1858 C/T, rs2476601) in 78 DNA samples from CF patients and 232 healthy controls from northeast Mexico using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method...
July 2016: Archives of Medical Research
Elsa Perrody, Laurence Abrami, Michal Feldman, Beatrice Kunz, Sylvie Urbé, Gisou van der Goot
Many membrane proteins fold inefficiently and require the help of enzymes and chaperones. Here we reveal a novel folding assistance system that operates on membrane proteins from the cytosolic side of the endoplasmic reticulum (ER). We show that folding of the Wnt signaling coreceptor LRP6 is promoted by ubiquitination of a specific lysine, retaining it in the ER while avoiding degradation. Subsequent ER exit requires removal of ubiquitin from this lysine by the deubiquitinating enzyme USP19. This ubiquitination-deubiquitination is conceptually reminiscent of the glucosylation-deglucosylation occurring in the ER lumen during the calnexin/calreticulin folding cycle...
October 18, 2016: ELife
Isabelle Sermet-Gaudelus, Martial Delion, Isabelle Durieu, Jacky Jacquot, Dominique Hubert
Low bone mineral density (BMD) is a common problem in adults with cystic fibrosis (CF), the etiology of which is multifactorial. In this study, we provide the first evidence that ivacaftor improves BMD in CF patients carrying the p.Gly551Asp mutation. Consistently, in vitro experiments with TNF-α-stimulated primary F508del-CFTR osteoblasts demonstrated that correction of p.Phe508del-CFTR markedly decreased RANKL protein production, a major factor of bone resorption. These clinical and fundamental observations suggest that rescue of mutated CFTR protein improves bone remodeling and support the link between CFTR and bone cell physiology...
October 10, 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Vito Terlizzi, Giuseppe Castaldo, Donatello Salvatore, Marco Lucarelli, Valeria Raia, Adriano Angioni, Vincenzo Carnovale, Natalia Cirilli, Rosaria Casciaro, Carla Colombo, Antonella Miriam Di Lullo, Ausilia Elce, Paola Iacotucci, Marika Comegna, Manuela Scorza, Vincenzina Lucidi, Anna Perfetti, Roberta Cimino, Serena Quattrucci, Manuela Seia, Valentina Maria Sofia, Federica Zarrilli, Felice Amato
BACKGROUND: The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. OBJECTIVES: To describe the genotype-phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator (CFTR) complex alleles. METHODS: We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p...
October 13, 2016: Journal of Medical Genetics
I C Sampaio, P H Q S Medeiros, F A P Rodrigues, P A Cavalcante, S A Ribeiro, J S Oliveira, M M G Prata, D V S Costa, S G C Fonseca, M M Guedes, A M Soares, G A C Brito, A Havt, S R Moore, A A M Lima
Undernutrition represents a major public health challenge for middle- and low-income countries. This study aimed to evaluate whether a multideficient Northeast Brazil regional basic diet (RBD) induces acute morphological and functional changes in the ileum of mice. Swiss mice (∼25 g) were allocated into two groups: i) control mice were fed a standard diet and II) undernourished mice were fed the RBD. After 7 days, mice were killed and the ileum collected for evaluation of electrophysiological parameters (Ussing chambers), transcription (RT-qPCR) and protein expression (western blotting) of intestinal transporters and tight junctions...
October 10, 2016: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Xin Meng, Jack Clews, Vasileios Kargas, Xiaomeng Wang, Robert C Ford
The cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for the disease cystic fibrosis (CF). It is a membrane protein belonging to the ABC transporter family functioning as a chloride/anion channel in epithelial cells around the body. There are over 1500 mutations that have been characterised as CF-causing; the most common of these, accounting for ~70 % of CF cases, is the deletion of a phenylalanine at position 508. This leads to instability of the nascent protein and the modified structure is recognised and then degraded by the ER quality control mechanism...
October 12, 2016: Cellular and Molecular Life Sciences: CMLS
W Joon Chung, Jennifer L Goeckeler-Fried, Viktoria Havasi, Annette Chiang, Steven M Rowe, Zackery E Plyler, Jeong S Hong, Marina Mazur, Gary A Piazza, Adam B Keeton, E Lucile White, Lynn Rasmussen, Allan M Weissman, R Aldrin Denny, Jeffrey L Brodsky, Eric J Sorscher
Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present...
2016: PloS One
Donna J Palmer, Nathan C Grove, Jordan Ing, Ana M Crane, Koen Venken, Brian R Davis, Philip Ng
Helper-dependent adenoviral vectors mediate high efficiency gene editing in induced pluripotent stem cells without needing a designer nuclease thereby avoiding off-target cleavage. Because of their large cloning capacity of 37 kb, helper-dependent adenoviral vectors with long homology arms are used for gene editing. However, this makes vector construction and recombinant analysis difficult. Conversely, insufficient homology may compromise targeting efficiency. Thus, we investigated the effect of homology length on helper-dependent adenoviral vector targeting efficiency at the cystic fibrosis transmembrane conductance regulator locus in induced pluripotent stem cells and found a positive correlation...
October 11, 2016: Molecular Therapy. Nucleic Acids
Stephanie Chin, Maurita Hung, Christine E Bear
Cystic fibrosis transmembrane conductance regulator (CFTR) channel gating is predominantly regulated by protein kinase A (PKA)-dependent phosphorylation. In addition to regulating CFTR channel activity, PKA phosphorylation is also involved in enhancing CFTR trafficking and mediating conformational changes at the interdomain interfaces of the protein. The major cystic fibrosis (CF)-causing mutation is the deletion of phenylalanine at position 508 (F508del); it causes many defects that affect CFTR trafficking, stability, and gating at the cell surface...
October 8, 2016: Cellular and Molecular Life Sciences: CMLS
Elvira Sondo, Emanuela Pesce, Valeria Tomati, Monica Marini, Nicoletta Pedemonte
BACKGROUND: Deletion of phenylalanine 508 is the most frequent mutation causing cystic fibrosis. It causes multiple defects: 1) misfolding of the protein causing retention at the ER (processing defect); 2) reduced channel activity (gating defect); 3) reduced plasma membrane residency time due to increased internalization rate and defective recycling. METHODS: Druggability of F508del-CFTR was demonstrated by several studies. Correctors are molecules able to improve maturation and trafficking to the membrane of F508del-CFTR...
October 6, 2016: Current Pharmaceutical Design
Isabelle Callebaut, Brice Hoffmann, Pierre Lehn, Jean-Paul Mornon
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a member of the ATP-binding cassette (ABC) transporter superfamily that functions as an ATP-gated channel. Considerable progress has been made over the last years in the understanding of the molecular basis of the CFTR functions, as well as dysfunctions causing the common genetic disease cystic fibrosis (CF). This review provides a global overview of the theoretical studies that have been performed so far, especially molecular modelling and molecular dynamics (MD) simulations...
October 7, 2016: Cellular and Molecular Life Sciences: CMLS
Mélanie Faria da Cunha, Juliette Simonin, Ali Sassi, Romain Freund, Aurélie Hatton, Charles-Henry Cottart, Nadia Elganfoud, Rachid Zoubairi, Corina Dragu, Jean Philippe Jais, Alexandre Hinzpeter, Aleksander Edelman, Isabelle Sermet-Gaudelus
The nasal epithelium of the mouse closely mimics the bioelectrical phenotype of the human airways. Ion transport across the nasal epithelium induces a nasal transepithelial potential difference. Its measurement by a relatively non-invasive method adapted from humans allows in vivo longitudinal measurements of CFTR-dependent ionic transport in the murine nasal mucosa. This test offers a useful tool to assess CFTR function in preclinical studies for novel therapeutics modulating CFTR activity. Here we extensively review work done to assess transepithelial transport in the murine respiratory epithelium in the basal state and after administration of CFTR modulators...
October 4, 2016: International Journal of Biochemistry & Cell Biology
Baoying Zheng, Ling Cao
Cystic fibrosis (CF) is rarely seen in Asian populations. We diagnosed two CF cases. One of them had a novel mutation c.870-1G>C in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There have been 38 Chinese CF patients reported in literature from 1974 until the present (2016), 25 different mutations were identified. Only one of these mutations (R553X) is in the Caucasian CF screening panel. The mutations identified in Chinese CF patients are very different from the common Caucasian gene mutations...
October 7, 2016: Pediatric Pulmonology
Lis C Puga Molina, Nicolás A Pinto, Paulina Torres Rodríguez, Ana Romarowski, Alberto Vicens Sanchez, Pablo E Visconti, Alberto Darszon, Claudia L Treviño, Mariano G Buffone
Mammalian sperm require to spend a limited period of time in the female reproductive tract to become competent to fertilize in a process called capacitation. It is well established that HCO3(-) is essential for capacitation because it activates the atypical soluble adenylate cyclase ADCY10 leading to cAMP production, and promotes alkalinization of cytoplasm and membrane hyperpolarization. However, how HCO3(-) is transported into the sperm is not well understood. There is evidence that CFTR activity is involved in the human sperm capacitation but how this channel is integrated in the complex signaling cascades associated with this process remains largely unknown...
October 7, 2016: Journal of Cellular Physiology
Vinciane Saint-Criq, Michael A Gray
Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations...
October 6, 2016: Cellular and Molecular Life Sciences: CMLS
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