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FLASH GENE
Symbol CFTR contributors: mct/ - updated : 13-01-2015
HGNC name cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)
HGNC id 1884
Corresponding disease
CBAVD congenital bilateral absence of the vas deferens
CF cystic fibrosis of pancreas
Location 7q31.2      Physical location : 117.120.016 - 117.308.716
Synonym name
  • ATP-binding cassette transporter sub- family C member 7
  • cAMP- dependent chloride channel
  • channel conductance-controlling ATPase
  • Synonym symbol(s) ABCC7, MRP7, CFTR/MRP, TNR-CFTR, ABC35, dJ760C5.1
    EC.number 3.6.3.49
    DNA
    TYPE functioning gene
    SPECIAL FEATURE
    text flanked by two genes ASZ1 [ankyrin repeat, SAM (sterile alpha-motif) and basic leucine zipper] and CTTNBP2 (cortactin-binding protein 2), which have very different expression profiles
    STRUCTURE 188.70 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   enhancer   transcription factor
    text structure
  • including multiple potential intragenic regulatory elements (DNase I hypersensitive) showing different patterns of cell-specific expression
  • cis-acting regulatory elements elsewhere in the locus, both flanking the gene and within introns, were potentially required to co-ordinate regulated, tissue-specific expression of CFTR
  • complex pattern of expression with both spatial and temporal regulation
  • in primary airway cells, skin fibroblasts, and both airway and intestinal cell lines, the CFTR promoter is unmethylated, irrespective of CFTR expression status
  • intronic elements that were associated with DNase I hypersensitive sites (DHS) and bound the hepatocyte nuclear factor 1 (HNF1), CDX2, and PBX1 implicated in the regulation of CFTR gene expression
  • four elements in a 460-kb region around the locus that loop specifically to the CFTR promoter exclusively in CFTR expressing cells, with DNase I hypersensitive sites and histone modification patterns characteristic of enhancers )
  • critical cis-regulatory element located in intron 11, 100 kb distal to the promoter, with which it interacts, containing an intestine-selective enhancer and associating with enhancer signature proteins, such as EP300, in addition to tissue-specific transcription factors (HNF1A, CDX2, FOXA1/FOXA2)
  • MAPPING cloned Y linked Y status confirmed
    Map cen - MET - D7S122 - D7S23 - D7S399 ,WNT2 - D7S633 - D7S677 /CFTR - D7S424 - D7S8 - D7S426 - qter
    Physical map
    ZNF277 7q31.1 zinc finger protein (C2H2 type) 277 IFRD1 7q31 interferon-related developmental regulator 1 FLJ39575 7q31.1 hypothetical protein FLJ39575 NPM1P14 7q31.1 nucleophosmin 1 (nucleolar phosphoprotein B23, numatrin) pseudogene 14 FLJ13576 7q31.32 hypothetical protein FLJ13576 FLJ31818 7q31.1 hypothetical protein FLJ31818 GPR85 7q31 G protein-coupled receptor 85 LOC389548 7 hypothetical gene supported by BX537645 PPP1R3A 7q11.23 protein phosphatase 1, regulatory (inhibitor) subunit 3A (glycogen and sarcoplasmic reticulum binding subunit, skeletal muscle) FOXP2 7q31 forkhead box P2 HIC 7q31.1 forkhead box P2 TFEC 7q31.2 transcription factor EC TES 7q31.2 testis derived transcript (3 LIM domains) CAV2 7q31.1-q31.2 caveolin 2 CAV1 7q31.2-q31.3 caveolin 1, caveolae protein, 22kDa MET 7q31.2-q31.3 met proto-oncogene (hepatocyte growth factor receptor) CAPZA2 7q31.2-q31.3 capping protein (actin filament) muscle Z-line, alpha 2 ST7 7q31.1-q31.3 suppression of tumorigenicity 7 WNT2 7q31 wingless-type MMTV integration site family member 2 GASZ 7q31.31 GASZ CFTR 7q31.3 cystic fibrosis transmembrane conductance regulator, ATP-binding cassette (sub-family C, member 7) CORTBP2 7q31.3 cortactin binding protein 2 LSM8 7q31.1-q31.3 LSM8 homolog, U6 small nuclear RNA associated (S. cerevisiae) ANKRD7 7q31 ankyrin repeat domain 7 KCND2 7q31-q32 potassium voltage-gated channel, Shal-related subfamily, member 2 TM4SF12 7 transmembrane 4 superfamily member 12 ING3 7q31 inhibitor of growth family, member 3 FLJ21986 7q31.32 hypothetical protein FLJ21986 WNT16 7q31 wingless-type MMTV integration site family, member 16 FAM3C 7q22.1-q31.1 family with sequence similarity 3, member C HCP19 7q31.32 cytochrome c, somatic pseudogene LOC136143 7q31.32 similar to ribosomal protein L18; 60S ribosomal protein L18 PTPRZ1 7q31.3 protein tyrosine phosphatase, receptor-type, Z polypeptide 1 AASS 7q31.3 aminoadipate-semialdehyde synthase LOC389549 7 similar to zinc finger protein 312; forebrain embryonic zinc finger CADPS2 7q31.1 Ca2+-dependent activator protein for secretion 2
    RNA
    TRANSCRIPTS type messenger
    text
  • two alternative upstream exons of the gene that were mutually exclusive with the first exon and one of which showed temporal regulation in the lung (PMID: 19855085)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 - 6132 - 1480 - 2008 18992954
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestine   highly
    Endocrinepancreas   highly
    Nervousnerve   highly
    Respiratorynosenasal septum    Homo sapiens
     respiratory tractbronchus    Homo sapiens
     respiratory tracttrachea    Homo sapiens
    Urinarybladder   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialabsorptive excretoryalveolar epithelium   Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveameloblast
    Digestiveodontoblast
    Nervousneuron
    Olfactoryepithelial cell
    Respiratoryepithelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N terminus mediates its direct interaction with STX16
  • two tandemly repeated polytopic membrane-spanning domains (MSDs) typical of ABC transporters, and a third NH(2)-terminal MSD, with six transmembrane segments (TM6)
  • two NBDs (nucleotide-binding domains), NBD1 and NBD2 (Walker B motif of NBD2 plays a key role in ATPase activity by the NBD1-NBD2 heterodimer), and binding of potentiators (molecules increasing the activity of CFTR) involves salt bridge formation with AAs of NBD1
  • two cytoplasmic nucleotide-binding fold domains (NBF), with C terminus of the first NBF being an important molecular site for the trafficking of CFTR protein, for the control of CFTR channel gating, and for the pharmacological effect of a dual activity agent
  • a regulatory (R) domain from N terminal TMD1-NBF1-R-TMD2-NBF2-C terminal cytoplasmic domain
  • two CSNK2A1 phosphorylation sites
  • conjugated GlycoP
    mono polymer homomer , dimer
    HOMOLOGY
    Homologene
    FAMILY
  • ABC transporter superfamily
  • ABCC family
  • CFTR transporter subfamily
  • CATEGORY transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    text
  • localized CFTR protein and mRNA signals to the cytoplasm of neurons in all regions of the brain, but not to glial cells
  • CFTR anion channel is localized in the apical membrane of airway epithelia
  • basic FUNCTION
  • cystic fibrosis transmembrane conductance regulator, cAMP-regulated chloride channel, having an ATPase and an adenylate kinase activity
  • epithelial chloride channel, regulator of separate ion channels through NBF1
  • might be implicated in the pathogenesis of primary sclerosing cholangitis
  • having critical role for completion of enamel mineralization and conceivably functions as a regulator of pH during rapid crystal growth
  • plays a role in fluid absorption in the distal air spaces of adult lung (importance of Cl- movement in alveolar fluid clearance may be, in part, the result of Cl-transport across alveolar type I cells)
  • implicated in transporting halides into the phagosomal lumen of neutrophils
  • cytosolic pH affects CFTR activity in multiple ways
  • role of CFTR and CLCN5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule
  • role of CFTR and soluble adenylyl cyclase in regulating the cAMP-CREB1 signaling pathway in Sertoli cells, defect of which may result in impaired spermatogenesis and azoospermia
  • CFTR predominately controls the rate of liquid secretion, whereas SLC26A4 regulates the composition of the secreted fluid and identifies a critical role for this anion exchanger in transcellular HCO3&
  • 8722; secretion in airway serous cells
  • both CFTR and ANO1 are separate molecular entities that show functional and molecular interaction
  • ATP-dependent gating of CFTR is potentially associated with the opening and closing of a gate within the permeation pathway at the level of these pore-lining amino acids
  • presence of CFTR on the plasma membrane influences the cytoskeletal organizational state and, consequently, cAMP distribution
  • lymphocyte CFTR promotes epithelial bicarbonate secretion for bacterial killing
  • can function as an adenylate kinase
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • significant role for the multiprotein complex CFTR-SLC9A3R1-EZR-actin in maintaining tight junctions organisation and barrier function, suggesting that the RHOA/ROCK pathway is involved
  • SLC26A8-CFTR complex impicated in the regulation of the chloride and bicarbonate fluxes required for sperm motility and capacitation
  • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP binding
  • interaction of nucleotide triphosphate with CFTR at ATP-binding site 2 is required for its adenylate kinase activity
  • protein
  • interacts with and regulates the activity of SLC4A7
  • endosomal SNARE proteins physically and functionally interact with CFTR
  • interacting with SLC9A3R1, SLC9A3R2, PDZK1 (SLC9A3R1, SLC9A3R2, and PDZK1, modulate CFTR membrane retention, conductivity, and interactions with other transporters)
  • SLC26A5 may interact physically with CFTR in the lateral membrane of OHCs (CFTR is capable of enhancing voltage-dependent charge displacement, a signature of OHC motility, whereas prestin does not affect the chloride conductance of CFTR)
  • interacting with Ig domains of FLNA
  • interacting with CELF2 (novel CFTR splice repressor protein that, depending on its level and type of intron 8 polymorphism, may impose a strong control of the amount of correctly spliced CFTR transcript in the region of exon 9
  • normally inhibits SCNN1A function in the airways, but in CF, where CFTR is mutated and nonfunctional, SCNN1A activity is enhanced
  • SCNN1A and CFTR physically associate in mammalian cells (limiting proteolytic cleavage of SCNN1A is a mechanism by which CFTR down-regulates Na+ absorption)
  • biochemical and functional association between CFTR and syntaxin 16 (STX16) that mediates vesicle transport within the early/late endosomes and trans-Golgi network
  • interacts with STX3
  • CSE1L is a negative regulator of CFTR-dependent fluid secretion
  • COMMD1 is a new CFTR partner, and CFTR is protected from ubiquitination by COMMD1, which sustains CFTR expression at the plasma membrane
  • central role for the IL13/IL13RA1 pathway in the regulation of intestinal epithelial cell Cl(-) secretion via up-regulation of CFTR, suggesting an important role for this pathway in secretory diarrhea
  • activates ORCC (outwardly rectifying chloride channel)
  • produced by ANO6
  • dual role for FKBP8 in regulating CFTR synthesis and post-translational folding
  • SLC26A8 and CFTR physically interact, and SLC26A8 expression strongly stimulates CFTR activity
  • 14-3-3 binding to phosphorylated CFTR augments its biogenesis by reducing retrograde retrieval of CFTR to the endoplasmic reticulum
  • acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl(-) channel, CFTR
  • SERP1 appears to promote expression of CFTR and is a novel cochaperone and regulator of SCNN1A, SCNN1B, SCNN1G expression
  • MIR138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis
  • PRKAA1 binds to and phosphorylates CFTR, attenuating PKA-activated CFTR gating
  • exists in a functional cellular complex with PRKAA1 and CFTR in airway epithelia, and its catalytic function is required for the PRKAA1-dependent regulation of CFTR
  • SLC9A3R1 is involved in PKA-dependent activation of CFTR by interacting with CFTR via its PDZ domains and with ezrin via its C-terminal domain
  • ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins GOPC and STX6
  • RNF185 and RNF5 are a novel E3 ligase module central to the control of CFTR degradation
  • glucocorticoid-induced increase in CFTR abundance requires phosphorylation of SHANK2 at an SGK1 consensus site
  • cell & other
    REGULATION
    inhibited by CALR
    STX8 (strong inhibition of CFTR chloride current by syntaxin 8 overexpression)
    Other reulated by STX16 (regulates CFTR activity by increasing surface abundance via its membrane trafficking SNARE function rather than directly affecting CFTR channel)
    regulated by the pH (pHi has multiple effects on CFTR activity)
    regulation of CFTR by SYK, a recognized controller of inflammation
    ASSOCIATED DISORDERS
    corresponding disease(s) CBAVD , CF
    related resource Cysticfibrosis
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    dDecreased CFTR and CREB1 expression are also observed in human testes with azoospermia
    Susceptibility maybe a susceptibility gene for sarcoidosis and susceptibility for pancreatic chronic idiopathic
    Variant & Polymorphism overexpression of splicing factors (cellular and viral) can modulate the splicing pattern
    Candidate gene
    Marker
  • may function as a novel tumor marker, and a prospective prognostic indicator for cervical cancer
  • Therapy target
    SystemTypeDisorderPubmed
    respiratoryCF (mucoviscidosis) 
    ion channel modulating agents, such as lancovutide (Moli1901, duramycin) and denufosol, which activate alternate (non-CF transmembrane regulator [CFTR]) chloride channels, and GS 9411, a sodium channel antagonist, are now at the stages of clinical study a
    cancerreproductiveuterus
    may function as a potential therapeutic target for cervical cancer
    ANIMAL & CELL MODELS
  • mice lacking functional CFTR (Cftrdelta508) have no lung phenotype but show similar ileal problems to humans, but properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer
  • severe osteopenia and altered bone architecture were found in young and mature adult F508del Cftr(tm1Eur) mice