II. BACKGROUND 
IIA Cystic Fibrosis 
Cystic fibrosis (CF) is monogenetic disorder that presents as a multisystem 
disease (1-6). The first signs and symptoms typically occur in childhood, but nearly 
3% of patients are diagnosed as adults. Due to improvements in therapy, more than 
25% of patients reach adulthood and >9% live past age 30. The disease is 
characterized by chronic airways infection that ultimately leads to bronchiectasis 
and bronchiolectasis, exocrine pancreatic insufficiency, abnormal sweat gland 
function, and urogenital dysfunction. 
IIA.1. Pathogenesis 
ILA.l.a. Genetic Basis: 
CF is an autosomal recessive disease resulting from mutations in the CF gene 
located on chromosome 7 (7-9). The prevalence of CF varies with the ethnic origin 
of a population. CF is detected in approximately 1 in 2,500 live births in the 
Caucasian population of North America and Northern Europe, 1 in 17,000 live 
births of African-Americans, and 1 in 90,000 live births of the Asian population of 
Hawaii. The most common mutation in the CF gene is a three-base pair deletion 
that results in absence of phenylalanine at amino acid position 508 (AF 508 ) of CF 
gene protein product, the CF transmembrane regulator (CFTR). 
ILA.l.b. CFTR Protein: 
The CFTR protein is a single polypeptide chain, containing 1480 amino acids 
that appears to function as a cyclic AMP-regulated CF channel. The fully processed 
form of CFTR is found in the plasma membrane in normal epithelia (10,11). 
Biochemical studies indicate that the AF 508 mutation leads to improper processing 
and intracellular degradation of the CFTR protein (12,13). Thus, absence of CFTR 
protein at appropriate cellular sites may be a part of the pathophysiology of CF. 
However, other mutations in the CF gene produce CFTR proteins that are fully 
processed but are nonfunctional at the appropriate cellular sites. 
IIA.1.C. Epithelial Dysfunction-General: 
The epithelia affected by CF exhibit in their native state different functions; 
i.e., some are volume absorbing (airways and intestinal epithelia), some are salt but 
not volume absorbing (sweat duct) whereas others are volume secretory (pancreas). 
Given this diverse array of native activities, it should not be surprising that CF 
produces very different effects on patterns of electrolyte and water transport 
(2,4,14). However, the unifying concept is that all affected tissues express abnormal 
cAMP-regulated Cl' channel activity. 
Recombinant DNA Research, Volume 17 
[437] 
