THE MOLECULAR-BASIS FOR DISEASE VARIABILITY IN CYSTIC-FIBROSIS

Cystic fibrosis (CF) is an autosomal recessive disorder caused by muta tions 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 it s mutations has promoted extensive research into the association betwe en genotype and phenotype. Several studies showed that there are mutat ions, like the Delta F508 (the most common mutation worldwide), which are associated with a severe phenotype and there are mutations associa ted with a milder phenotype. However, there is a substantial variabili ty in disease expression among patients carrying the same mutation. Th is variability involves also the severity of lung disease. Furthermore , increased frequencies of mutations are found among patients with inc omplete CF expression which includes male infertility due to congenita l 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 di srupt CFTR function are defective protein production, processing, chan nel regulation, and conductance. In addition, reduced levels of the no rmal 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 diseas e expression is associated with different levels of normally spliced t ranscripts. Further understanding the mechanisms of CFTR dysfunction m ay suggest different therapeutic strategies for each class of mutation s.