Molecular Mechanisms of CFTR Chloride Channel Dysfunction in Cystic Fibrosis

Michael J. Welsh’ and Alan E. Smith+ ‘ Howard Hughes Medical Institute Departments of Internal Medicine and of Physiology and Biophysics University of Iowa College of Medicine Iowa City, Iowa 52242 fGenzyme Corporation One Mountain Road Framingham, Massachusetts 01701 in the last few years, there has been substantial progress in understanding cystic fibrosis (CF). CF was first described as a clinical syndrome in 1938, and an appreciation of its autosomal recessive nature followed shortly thereafter. The disease is usually manifested as exocrine pancreatic insufficiency, an increase in the sweat Cl- concentration, male infertility, and airway disease. Airway disease leads to progressive lung dysfunction, which is currently the major cause of morbidity and is responsible for 95% of CF mortality (Boat et al., 1989). Defective Cl- transport across affected epithelia is the hallmark of the disease (reviewed by Quinton, 1990) although numerous other abnormalities have been described (reviewed by Tsui and Buchwald, 1991). The gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) has been identified (Riordan et al., 1989) and over 200 CF-associated mutations within the gene have since been reported (Tsui, 1992). CFTR is a regulated Cl- channel, for which structure-function relationships have begun to be established (reviewed by Welsh et al., 1992). CFTR is predicted to consist of five domains (Figure 1): two membrane- spanning domains, each composed of six putative transmembrane segments; two nucleotide-binding domains; and a unique regulatory(R) domain. Insight into the functions of individual domains has come from a number of studies. The membrane-spanning domains appear to contribute to the formation of the Cl- channel pore, since mutation of specific residues within the first membrane-spanning domain alters the anion selectivity of the channel. The nucleotide-binding domains control