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GENATLAS PHENOTYPE
last update : 05-06-2012
Symbol CF
Location 7q31.2
Name cystic fibrosis of pancreas
Other name(s) mucoviscidosis
Corresponding gene CFTR
Other symbol(s) FKP
Main clinical features
  • pulmonary disease is the major cause of morbidity and mortality with chronic bronchopulmonary infection progressing to end-stage lung disease
  • pancreatic insufficiency with malabsorption in most patients
  • meconium ileus at birth in 15-20 percent of cases
  • sweat glands and biliary tree are also affected
  • infertility may occur in males and females
    • Genetic determination autosomal recessive
    Prevalence 1 in 3200 livebirths with heterozygote frequency of 1 in 28 in Caucasian population, lower in other ethnic groups
    Related entries CBAVD, CFM1
    Function/system disorder metabolism/membrane transport
    multisystem/generalized
    Type disease
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    various types     more than 1000 mutations identified, mostly point mutations or small deletions, the recommended mutation panel comprise 23-25 mutations
    deletion     . the most common mutation is delta F508 (66 percent frequency in Caucasians) . this variant failed to achieve an energetically favorable fold that may be responsible for the pathophysiology
    repeat expansion     poly T/TG tract in intron 8, the 5T variant has an adverse effect on proper exon 8 splicing
    deletion     gross genomic rearrangements involving simple or complex deletions could account for 20 percent of unidentified CF chromosomes
    abnormal splicing   abnormal protein/loss of function 13p100 of CFTR mutations are classified as "splicing mutations (PMID: 19759008)
    Remark(s)
  • CF is the most common life-limiting autosomal recessive disorder in Caucasian population. Patients may be homozygotes for a mutation or compound heterozygotes
  • most common mutation, DeltaF508 omits the phenylalanine residue at position 508 in the first nucleotide binding domain (NBD1) of CFTR; mutant protein is retained in the endoplasmic reticulum and degraded by the ubiquitin-proteasome system
  • mutant protein delta F508 fails to fold properly and is targeted for proteosomal degradation.;G551D, the second most common mutation, causes loss of function of the protein at the plasma membrane (PMID: 19837664))
  • mutation delta F508 results in disruption of the energetics of the protein fold, leading to efficient degradation of CFTR in the endoplasmic reticulum, but posible restoration of deltaF508 CFTR function in primary lung epithelial cells through HDACi-sensitive mechanisms (PMID: 19966789))
  • {Delta}F508 mutation in CFTR down regulates the antigen presentation pathway, impairs immune function in airway epithelial cells but may not increase inflammation (PMID: 20044437))
  • (deltaF508), the most prevalent mutation, causes a temperature-sensitive folding defect, and instability was attributed to unfolding and subsequent ubiquitination, internalization, and lysosomal degradation
  • loss of anion transport is key to airway epithelial dysfunction in CF (PMID: 21646513))
  • F508del mutation in accounts for most of Caucasian CF genotypes and results in dysfunctional chloride secretion in pulmonary epithelium, leading to a severe and chronic lung inflammation and bacterial infection
  • the F508del mutation in CFTR impacts trabecular bone mass by reducing bone formation (PMID:22449949))
  • SPNS2 transporter contributes to the accumulation of S1P in Cystic Fibrosis human bronchial epithelial cells (PMID: 34572307))
    • Genotype/Phenotype correlations usually poor for pulmonary disease, but compound heterozygotes with delF508/A455E are less affected than delF508 homozygous individuals and the 5T variant in cis configuration with the R117H mutation influence the severity of lung disease. Modifier genes have been proposed to explain the great variability of phenotype: TGFB1, SCNN1B, SCNN1G, TNRSF1A; comparing mildly and severely affected cystic fibrosis sib pairs identify a paternally imprinted locus on 7q34 as a modulator of cystic fibrosis disease severity (PMID: 20051989)) Correlation is better in the context of pancreatic function with common mutations classified as pancreatic sufficient (PS) or pancreatic insufficient (PI)