[Molecular basis of phenotype heterogeneity in cystic fibrosis]

The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the cystic fibrosis phenotype, was cloned and sequenced in 1989. Since then, more than 650 mutations have been reported. The analysis of the entire coding sequence of the CFTR gene (27 exons) has been able to characterize more than 90% of the mutations in different populations. Moreover, screening of the entire coding and flanking sequences of the CFTR gene in males with congenital bilateral absence of the vas deferens revealed that 80% of these subjects are at least heterozygous for a CF mutation. These results help to improve genetic counselling and prenatal diagnosis of cystic fibrosis. Different studies examining the relation between phenotype and genotype in CF with respect to AF508 or non delta F508 mutations have demonstrated that some "severe" mutations are strongly associated with pancreatic insufficiency or complications. It has been also showed a relationship between the presumed severity of the mutations and the observed phenotype, not only for pancreatic status, but also for the severity of the respiratory involvement. However, some studies found that some individuals do not fit the outcome of their general group of genotype. These findings reinforce the conviction that other factors besides the CFTR mutation are involved in the severity and outcome of the disease.