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Cystic fibrosis (CF) is the most common lethal genetic condition in the Caucasian population. Significant progress has been made in diagnosis and treatment, which has led to dramatically increased survival and reduced morbidity rates. The localization of the gene encoding the CF transmembrane conductance regulator (CFTR) in 1989 enabled a deeper understanding of the disease pathophysiology and led to the development of novel therapeutic avenues correcting the basic defect instead of fire-fighting the downstream consequences of the disease.
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CF is an autosomal recessive disorder reported in virtually every ethnic and racial group around the world. The estimated prevalence in those of northern European descent is approximately 1 in 3200. There is a marked variation in prevalence throughout the world; the disease is much less frequent in African Americans, with a prevalence of 1 in 17,000, and is even rarer in Asians. The carrier frequency is approximately 1 in 20 in Caucasians, approximately 1 in 46 in Hispanics, 1 in 65 in Africans, and 1 in 90 in Asians.
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CFTR is a member of the ATP-binding cassette subfamily C (ABCC7). The gene is located on chromosome 7q31.2 and spans approximately 250 kb of deoxyribonucleic acid with 27 exons, which are separated by large introns. The CFTR gene encodes a transmembrane glycoprotein of 1480 amino acids called the CFTR protein, which is expressed on the apical membrane of epithelial cells, which involves a number of crucial pathways. The gene is first transcribed into messenger RNA (mRNA) and then transported to the endoplasmic reticulum (ER), where it is translated into protein. Immature CFTR protein undergoes folding, oligomerization, and maturation in the ER. Mature CFTR protein is transported first to the Golgi apparatus for final processing, and then to the cell surface, where it plays an important role in both secretion and reabsorption of ions (in particular chloride) and water at epithelial surfaces, depending on the electrochemical gradient present.
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Since the identification of the CFTR gene defect, approximately 2000 mutations of the CF locus have been identified. However, the majority of these mutations are not only rare, but also their functional and clinical consequences are unknown. Consequently, the CFTR2 Database was established to provide detailed and expert-reviewed functional and clinical information on CFTR mutations (http://www.cftr2.org). To date, more than 140 CFTR mutations have been confirmed as causing disease. The most common mutation identified worldwide is the F508del mutation (c.1521_1523delCTT; p.Phe508del according to the current standard nomenclature), found in approximately 85% of Caucasian CF patients (Table 507-1).
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