Cystic fibrosis (CF) is a common inherited disease that has a high frequency in Caucasians. The disorder affects all exocrine glands, with symptoms involving the lungs and pancreas usually dominating the clinical picture. Even though the gene responsible for CF and its gene product, an integral membrane glycoprotein, have been identified, two aspects of the disease make CF particularly difficult to both diagnose and manage. First, there is tremendous variability in the degree and pattern of involvement of organs in different persons. In addition, we lack information about the precise details of the molecular and cellular pathogenesis of the disease. This chapter focuses on the pathophysiology and management of CF. Our current understanding of the genetics and underlying molecular biology is highlighted. Complications of the disorder are addressed, and a brief discussion of relevant psychosocial and reproductive issues is provided. Finally, potential future directions in treatment are described.
CF demonstrates an autosomal-recessive pattern of inheritance. In the United States, the incidence of the disease is approximately 1 in 3000 in Caucasians, 1 in 6000 in Hispanics, and 1 in 10,000 in African Americans. The frequency of unaffected heterozygote carriers of a CF mutation is estimated to be 1 in 26 in persons of Northern European ancestry.
CF is caused by mutations in a single gene named the cystic fibrosis transmembrane conductance regulator (CFTR). This gene was identified with an approach known as positional cloning, which permitted mapping of the gene, without prior knowledge of the biochemical defect, through use of polymorphic DNA markers. The first genetic marker that was found to be linked to CF was paraoxonase. In 1985, the demonstration of the linkage of CF to two DNA markers, D7S15 and D7S8, and to the met oncogene established the localization of the CF gene to the long arm of chromosome 7. Following a series of molecular cloning experiments, which included “chromosome walking” and “jumping,” a candidate gene was identified. This was proved to be the CF gene in 1989, largely through the discovery of a frequent mutation.1,2
The CF gene spans approximately 230 kb of DNA and contains 27 exons. The mRNA is 6.5 kb and is detected in a variety of tissues, including lungs, pancreas, and sweat glands, which are predominantly affected in pathogenesis of the disease. The deduced polypeptide was predicted to be an integral membrane glycoprotein containing 1480 amino acids (Fig. 50-1) (see “Pathogenesis” below). Several major and minor splicing variants in the transcripts have been described in individuals with and without CF. In most cases, however, the significance of the alternative splicings is not clear.
Domain model of the cystic fibrosis transmembrane conductance regulator (CFTR). Based on hydrophobicity plots, CFTR has 12 transmembrane-spanning domains, two nucleotide (N) binding domains (NBD 1 and NBD 2), and a regulatory (R) domain. The 12 transmembrane domains form ...