Chapter 201

## Abstract

1. Cystic fibrosis (CF) is a lethal autosomal recessive disease affecting primarily Caucasian populations. The incidence is one in 2000 to 3000 births in various groups.

2. CF affects epithelia in several organs. Most of the current morbidity and mortality results from impairment of the pulmonary defense system leading to chronic infection and neutrophil-dominated inflammation of the small and large airways. Persistent infections, especially with Pseudomonas aeruginosa and Staphylococcus aureus cause chronic sputum production, airway obstruction, and eventually bronchiectasis and lung destruction. Exocrine pancreatic insufficiency occurs in approximately 85 percent of patients. The resulting deficiency of pancreatic enzyme secretion causes malabsorption of fat, steatorrhea, and poor weight gain. Meconium ileus, present in approximately 10 to 20 percent of patients at birth, is often diagnostic of the illness. Almost all males with CF are infertile due to congenital malformation of the reproductive tract. Other manifestations include focal biliary cirrhosis and excessive salt loss from the sweat glands.

3. CF is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The gene contains 27 exons encompassing approximately 250 kb of DNA on chromosome 7q31.2. More than 800 disease-associated mutations have been discovered in the gene. The most common mutation, deletion of phenylalanine at position 508 (ΔF508), accounts for nearly 70 percent of mutations in European-derived Caucasian populations. Only four other mutations individually account for more than 1 percent of CF alleles worldwide. The vast majority of mutations are uncommon worldwide, although they may occur in higher frequency in selected populations.

4. The diagnosis of CF is based on two criteria; presence of at least one characteristic clinical feature and evidence of CFTR dysfunction. Clinical features include: (i) chronic sinopulmonary disease including persistent colonization/infection of the airways; (ii) gastrointestinal and nutritional abnormalities including meconium ileus, pancreatic insufficiency, focal biliary cirrhosis, and failure to thrive; (iii) salt loss syndromes; (iv) obstructive azoospermia; (v) a history of CF in a sibling or a positive newborn screening test result. CFTR dysfunction can be documented by: (i) elevated sweat Cl concentration; (ii) identification of disease-causing mutations in each CFTR gene; or (iii) demonstration of abnormal ion transport across the nasal epithelium.

5. CFTR is a member of the ATP-binding cassette (ABC) transporter family of membrane proteins. CFTR forms a regulated cell membrane Cl channel with five domains. Two membrane spanning domains, each comprising six transmembrane sequences, form a Cl channel pore. cAMP-dependent phosphorylation of the regulatory (R) domain governs channel activity, and ATP-binding and hydrolysis by two nucleotide binding domains control channel gating. CFTR may also influence the function of other membrane proteins including outwardly-rectifying Cl channels, the epithelial Na+ channel (ENaC), K+ channels, and the Cl/HCO3 exchanger. Linkage of CFTR to the cytoskeleton may influence its localization and function.

6. Mutations in the gene encoding CFTR disrupt CFTR function by four general mechanisms. Class I mutations, including premature termination signals and splicing abnormalities, severely reduce protein production. Class II mutations cause defective folding and disruption of protein biosynthesis. The common ΔF508 mutation does not escape from the endoplasmic reticulum and travel to the apical membrane because of a Class II defect. Class III mutations generate protein that reaches the plasma membrane but the channels show defective regulation. Class IV mutations generate correctly localized CFTR with defective pore properties. Individual mutations may have more than one effect.

7. CF epithelia show defective electrolyte transport across the apical membrane, which contributes to the pathogenesis of the disease in the sweat gland, pancreas, intestine, male genital tract, and hepatobiliary system. In the airways, defective electrolyte transport alters the airway surface liquid. The pathogenesis of CF airway disease is complex, but may include defective antimicrobial activity in airway surface liquid, altered mucociliary clearance, abnormal submucosal gland function, an enhanced inflammatory response, and other abnormalities.

8. The nature of mutations in CFTR are correlated with the severity of pancreatic disease and degree of sweat Cl abnormality. The relationship between genotype and pulmonary phenotype is less robust, likely due to the influence of genetic modifiers and the environmental factors.

9. Treatment of CF requires a comprehensive approach to prevention and treatment of pulmonary disease, nutritional status, gastrointestinal disease, and multiple other manifestations in children and adults. Antibiotics, airway clearance techniques, and anti-inflammatories remain the cornerstone for treating lung disease. Pancreatic enzyme replacement is the foundation for treating the pancreatic insufficiency. Recent advances in understanding the cellular and molecular basis of the disease and the pathophysiology are leading to the development of gene therapy and novel pharmacologic approaches to treatment.

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