The molecular basis for disease variability in cystic fibrosis

Eur J Hum Genet. 1996;4(2):65-73. doi: 10.1159/000472174.


Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The disease is characterized by a wide variability of clinical expression. The cloning of the CFTR gene and the identification of its mutations has promoted extensive research into the association between genotype and phenotype. Several studies showed that there are mutations, like the delta F508 (the most common mutation worldwide), which are associated with a severe phenotype and there are mutations associated with a milder phenotype. However, there is a substantial variability in disease expression among patients carrying the same mutation. This variability involves also the severity of lung disease. Furthermore, increased frequencies of mutations are found among patients with incomplete CF expression which includes male infertility due to congenital bilateral absence of the vas deferens. In vitro studies of the CFTR function suggested that different mutations cause different defects in protein production and function. The mechanisms by which mutations disrupt CFTR function are defective protein production, processing, channel regulation, and conductance. In addition, reduced levels of the normal CFTR mRNA are associated with the CF disease. These mutations are associated with a highly variable phenotype from healthy individuals or infertile males to a typical CF disease. This variability in disease expression is associated with different levels of normally spliced transcripts. Further understanding the mechanisms of CFTR dysfunction may suggest different therapeutic strategies for each class of mutations.

Publication types

  • Review

MeSH terms

  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / physiopathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Genetic Variation
  • Genotype
  • Humans
  • Male
  • Mutation
  • Phenotype
  • Vas Deferens / physiopathology


  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator