The relationship between genotype and phenotype in cystic fibrosis

Cystic fibrosis is characterized by a wide variability of clinical expression. The cloning of the cystic fibrosis transmembrane conductance regulator 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, such as delta F508 (the most common mutation worldwide), that are associated with a severe phenotype: early age at diagnosis, pancreatic insufficiency, poor nutritional status, high incidence of meconium ileus, and high sweat chloride levels; lung disease, however, is variable. The milder mutation is dominant over the severe mutation causing a milder phenotype. In vitro studies of cystic fibrosis transmembrane conductance regulator function suggested that different mutations cause different defects of protein production and function. Five mechanisms by which mutations disrupt cystic fibrosis transmembrane conductance regulator function have been suggested: class I mutations cause defective protein production, class II mutations are associated with defective protein processing, class III mutations are associated with defective regulation, class IV mutations are associated with defective conductance, and class V mutations include mutations affecting the level of normal messenger RNA transcript and protein required for normal function. This class might include mutations affecting correct splicing of pre-messenger RNA transcripts by either exon skipping or by inclusion of extra cryptic exons.