Eugene H Lewis III Myra J Lewis Jean A Amos and Gregory J Tsongalis


Cystic fibrosis (CF), a clinically heterogeneous disease, is the first genetic disease for which adult population screening has been initiated in the United States. Since the discovery of the CFTR gene in 1989, much has been learned about the pathophysiology and molecular genetics of this disorder. This review includes an overview of the genetics of CF, a discussion of pathophysiology, and clinical and anatomic pathology and concludes with a review of molecular diagnostics.


Cystic fibrosis is the most common lethal autosomal-recessive disease in individuals of European decent with a prevalence of 1 in 2500 to 3300 live births. Although most common in the Caucasian population, it has become apparent that members of other racial and ethnic backgrounds are also at risk (1). Approximately 30,000 children and adults in the United States are affected, and approx 850 individuals are newly diagnosed annually with the majority of those less than 1 yr of age.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene, the gene responsible for CF, spans approx 230 kb on chromosome 7q. This gene consists of 27 coding exons that result in a 6.5-kb mRNA product and a CFTR membrane glycoprotein of 1480 amino acids with a mass of approx 170,000 Da (2-4). CFTR functions as a cAMP- regulated chloride channel in the apical membrane of epithelial cells (5).

To date, over 1000 unique mutations in the CFTR gene have been described (6). The most common mutation is the deletion of phenylalanine at position 508 (AF508) and affects 70% of patients worldwide. Approximately half of CF patients are AF508 homozygotes. However, the majority of mutations are private, occurring only in single families, or are rare. G542X is the most frequent Caucasian mutation after AF508, occurring at a frequency of 2%. The allelic frequency of CFTR mutations varies by ethnic group, where, for example, AF508 is only present in 30% of the Ashkenazi Jewish population.

The mutations in the CFTR gene are grouped into six classes. These include class I (defective protein synthesis, where there is no CFTR protein at the apical membrane), class II

(abnormal/ defective processing and trafficking, where there is no CFTR protein at the apical membrane), class III (defective regulation, where there is a normal amount of nonfunctional CFTR at the apical membrane), class IV (decreased conductance, where there is a normal amount of CFTR with some residual function at the apical membrane), class V (reduced or defective synthesis/trafficking, where there is a decreased amount of functional CFTR at the apical membrane), and class VI (decreased stability, where there is a functional but unstable CFTR at the apical membrane) (7,8). Of the CFTR mutations, classes I-III are the most common and are associated with pancreatic insufficiency (9). The most common mutation worldwide is the AF508, class II, with varying frequency among ethnic groups (10).

Mutations in the CFTR gene can lead to an abnormal protein that causes defective electrolyte transport and defective chloride ion transport in apical membrane epithelial cells affecting the respiratory tract, pancreas, intestine, male genital tract, hepatobiliary system, and the exocrine system, resulting in complex multisystem disease. CFTR is a member of an ATP-binding cassette family with diverse functions such as ATP-dependent transmembrane pumping of large molecules, regulation of other membrane transporters, and ion conductance. The loss of CFTR-mediated anion conductance explains a variety of CF symptoms, including elevated sweat chloride because of defective salt absorption by the sweat ducts and meconium ileus because of defective fluid secretion by intestinal crypt cells (11). The malfunction of CFTR as a regulator of amiloride-sensitive epithelia Na+ channel leads to increased Na+ conductance in CF airways, which drives increased absorption of Cl- and water. Most symptoms of CF, such as meconium ileus, loss of pancreatic function, degeneration of the vas deferens, thickened cervical mucus, and failure of adrenergically mediated sweating are the result of the role CFTR plays in Cl-driven fluid secretion.

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