The Genetics of CFTR: Genotype - Phenotype Relationship, Diagnostic Challenge and Therapeutic Implications

Cystic fibrosis (CF; OMIM 602421, see OMIM link in the website section) is the most common lethal genetic disease of the Caucasian population, with a very variable prevalence, from 1/25000 to 1/900, depending on the geographical region (O'Sullivan & Freedman, 2009; Riordan, 2008). CF is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (Kerem et al., 1989; Rommens et al., 1989; Zielenski et al., 1991) (see Ensembl link in the website section), which encodes for a transmembrane multifunctional protein expressed mainly in epithelia (Trezise et al., 1993a; Yoshimura et al., 1991b) but also in several cell types of nonepithelial origin (Yoshimura et al., 1991a). It is an ATPand cAMP-dependent Clchannel with the main function performed at the apical membrane of epithelial cells. This function is the Clion secretion in the colon and airways, or its reabsorption in sweat glands (Riordan, 2008; Vankeerberghen et al., 2002). In the lung, the main targeted organ of CF, an additional crucial function performed by CFTR is the regulation of the epithelial Na+ channel (ENaC) activity. The exact mechanism of CFTR – ENaC interaction is not completely understood and contrasting evidences exist about the role of ENaC in CF. The most reliable vision of the basic defect is that, in the airway epithelia of CF patients, a CFTR deficiency causes an anomalous dual ion transport associated to an altered water absorption (Mall et al., 1998; Stutts et al., 1995; Berdiev et al., 2009) that, in turn, leads to sticky mucus and impaired mucociliary clearance (Donaldson et al., 2002; Matsui et al., 1998). The immune response greatly contributes to increased mucus viscosity through bacterial lysis and DNA release, as well as through immune cell death in the airways. Bacterial infections and inflammation produce bronchial obstruction, bronchiectasis, atrophy and, eventually, lung insufficiency. A probably non-exhaustive list of other CFTR functions includes: the bicarbonate secretion (Kim & Steward, 2009); the regulation of several other ionic channels and of the ion composition of intracellular compartments, as well the control of intracellular vesicle transport (Vankeerberghen et al., 2002); antibacterial activity exerted by epithelial cells (Pier et al., 1997; Schroeder et al., 2002) and macrophages (Del Porto et al., 2011; Di et al., 2006); maintenance of a correct level of hydration, essential for a physiologic development of male reproductive apparatus (Dube et al., 2008; Patrizio & Salameh, 1998; Trezise et al., 1993a), testis, pancreas, liver and intestine (O'Sullivan & Freedman, 2009; Ratjen & Doring, 2003); critical role in