Cystic fibrosis: Genetics and pathogenesis
- Julie P Katkin, MD
Julie P Katkin, MD
- Associate Professor of Pediatrics
- Baylor College of Medicine
Cystic fibrosis (CF) is a multisystem disease affecting the digestive system, sweat glands, and the reproductive tract, but progressive lung disease continues to be the major cause of morbidity and mortality. Patients with CF have abnormal transport of chloride and sodium across the respiratory epithelium, resulting in thickened, viscous airway secretions [1,2]. Over a highly variable time course ranging from months to decades after birth, individuals eventually develop chronic infection of the respiratory tract with a characteristic array of bacterial flora, leading to progressive respiratory insufficiency and eventual respiratory failure .
The genetics and pathogenesis of cystic fibrosis are discussed here. Details of the clinical manifestations and effects of the disease process are discussed separately. (See "Cystic fibrosis: Overview of gastrointestinal disease" and "Cystic fibrosis: Clinical manifestations of pulmonary disease".)
CF is caused by mutations in a single large gene on chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein [4-9]. Clinical disease requires disease-causing mutations in both copies of the CFTR gene.
The normal CFTR gene — CFTR belongs to the ABC (ATP-Binding Cassette) family of proteins, a large group of related proteins that share transmembrane transport functions. ABC proteins include bacterial transporters for amino acids and other nutrients, surfactant transport proteins, and the mammalian multidrug resistance (MDR) protein (or P-glycoprotein).
CFTR functions as a regulated chloride channel, which, in turn, may regulate the activity of other chloride and sodium channels at the cell surface [10-13]. The CFTR gene spans 250 kilobases on chromosome 7, encoding 1480 amino acids in the mature protein (figure 1). The protein has two groups of six membrane-spanning regions, two intracellular nucleotide-binding folds (NBFs), and a highly charged "R domain" containing multiple phosphorylation sites. Activation of the chloride channel requires phosphokinase A-mediated phosphorylation of the R domain, and the continuous presence of ATP in the NBFs [14,15].
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- The normal CFTR gene
- Genetic changes in CFTR
- - Class I mutations: Defective protein production
- - Class II mutations: Defective protein processing
- - Class III mutations: Defective regulation
- - Class IV mutations: Defective conduction
- - Class V mutations: Reduced amounts of functional CFTR protein
- GENE MODIFIERS
- INCOMPLETE PHENOTYPE
- DISEASE PATHOGENESIS
- Abnormal secretions
- - Gastrointestinal effects
- - Chronic lung infection