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 lungs, digestive system, sweat glands, and the reproductive tract. Patients with CF have abnormal transport of chloride and sodium across secretory epithelia, resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestines, and reproductive system [1,2]. Although the disease is systemic, progressive lung disease continues to be the major cause of morbidity and mortality for most patients. 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].
- Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352:1992.
- Ratjen F, Döring G. Cystic fibrosis. Lancet 2003; 361:681.
- Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168:918.
- Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science 1992; 256:774.
- Drumm ML, Collins FS. Molecular biology of cystic fibrosis. Mol Genet Med 1993; 3:33.
- Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245:1066.
- Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245:1073.
- Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245:1059.
- Bear CE, Li CH, Kartner N, et al. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 1992; 68:809.
- Guggino WB, Banks-Schlegel SP. Macromolecular interactions and ion transport in cystic fibrosis. Am J Respir Crit Care Med 2004; 170:815.
- Johnson LG, Boyles SE, Wilson J, Boucher RC. Normalization of raised sodium absorption and raised calcium-mediated chloride secretion by adenovirus-mediated expression of cystic fibrosis transmembrane conductance regulator in primary human cystic fibrosis airway epithelial cells. J Clin Invest 1995; 95:1377.
- Stutts MJ, Canessa CM, Olsen JC, et al. CFTR as a cAMP-dependent regulator of sodium channels. Science 1995; 269:847.
- Goldman MJ, Yang Y, Wilson JM. Gene therapy in a xenograft model of cystic fibrosis lung corrects chloride transport more effectively than the sodium defect. Nat Genet 1995; 9:126.
- Anderson MP, Berger HA, Rich DP, et al. Nucleoside triphosphates are required to open the CFTR chloride channel. Cell 1991; 67:775.
- Rich DP, Gregory RJ, Anderson MP, et al. Effect of deleting the R domain on CFTR-generated chloride channels. Science 1991; 253:205.
- Mickle JE, Cutting GR. Genotype-phenotype relationships in cystic fibrosis. Med Clin North Am 2000; 84:597.
- Correlation between genotype and phenotype in patients with cystic fibrosis. The Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med 1993; 329:1308.
- de Gracia J, Mata F, Alvarez A, et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax 2005; 60:558.
- McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet 2003; 361:1671.
- Decaestecker K, Decaestecker E, Castellani C, et al. Genotype/phenotype correlation of the G85E mutation in a large cohort of cystic fibrosis patients. Eur Respir J 2004; 23:679.
- Sosnay PR, Siklosi KR, Van Goor F, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 2013; 45:1160.
- Abeliovich D, Lavon IP, Lerer I, et al. Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population. Am J Hum Genet 1992; 51:951.
- Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med 2004; 6:387.
- Kerem E. Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy. Pediatr Pulmonol 2005; 40:183.
- Moskowitz SM. CFTR-related disorders www.genetests.org (Accessed on February 25, 2010).
- Lukacs GL, Durie PR. Pharmacologic approaches to correcting the basic defect in cystic fibrosis. N Engl J Med 2003; 349:1401.
- Fanen P, Hasnain A. Cystic fibrosis and teh CFTR gene. Atlas of Genetic and Cytogenetic Oncology and Hematology, 2001. Available at: http://documents.irevues.inist.fr/bitstream/handle/2042/37827/09-2001-CistFibID30032EL.pdf?sequence=3 (Accessed on February 08, 2013).
- Antunovic SS, Lukac M, Vujovic D. Longitudinal cystic fibrosis care. Clin Pharmacol Ther 2013; 93:86.
- Kerem E, Kerem B. Genotype-phenotype correlations in cystic fibrosis. Pediatr Pulmonol 1996; 22:387.
- Koch C, Cuppens H, Rainisio M, et al. European Epidemiologic Registry of Cystic Fibrosis (ERCF): comparison of major disease manifestations between patients with different classes of mutations. Pediatr Pulmonol 2001; 31:1.
- Dorfman R, Sandford A, Taylor C, et al. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest 2008; 118:1040.
- Drumm ML, Konstan MW, Schluchter MD, et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005; 353:1443.
- Garred P, Pressler T, Madsen HO, et al. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest 1999; 104:431.
- Boyle MP. Nonclassic cystic fibrosis and CFTR-related diseases. Curr Opin Pulm Med 2003; 9:498.
- Groman JD, Karczeski B, Sheridan M, et al. Phenotypic and genetic characterization of patients with features of "nonclassic" forms of cystic fibrosis. J Pediatr 2005; 146:675.
- Groman JD, Meyer ME, Wilmott RW, et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med 2002; 347:401.
- Cystic Fibrosis Foundation, Borowitz D, Parad RB, et al. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J Pediatr 2009; 155:S106.
- Kent G, Iles R, Bear CE, et al. Lung disease in mice with cystic fibrosis. J Clin Invest 1997; 100:3060.
- Gosselin D, Stevenson MM, Cowley EA, et al. Impaired ability of Cftr knockout mice to control lung infection with Pseudomonas aeruginosa. Am J Respir Crit Care Med 1998; 157:1253.
- Yarden J, Radojkovic D, De Boeck K, et al. Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype. Thorax 2005; 60:320.
- Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004; 350:560.
- Boucher RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004; 23:146.
- Ernst RK, Yi EC, Guo L, et al. Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa. Science 1999; 286:1561.
- Smith JJ, Travis SM, Greenberg EP, Welsh MJ. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 1996; 85:229.
- Donaldson SH, Boucher RC. Sodium channels and cystic fibrosis. Chest 2007; 132:1631.
- Guggino WB. Cystic fibrosis and the salt controversy. Cell 1999; 96:607.
- Cohen TS, Prince A. Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med 2012; 18:509.
- Griese M, Kappler M, Gaggar A, Hartl D. Inhibition of airway proteases in cystic fibrosis lung disease. Eur Respir J 2008; 32:783.
- Davis PB. Pathophysiology of the lung disease in cystic fibrosis. In: Cystic Fibrosis, Davis PB (Ed), Marcel Dekker, New York 1993. p.193.
- Armstrong DS, Grimwood K, Carlin JB, et al. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997; 156:1197.
- Heeckeren A, Walenga R, Konstan MW, et al. Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa. J Clin Invest 1997; 100:2810.
- DiMango E, Ratner AJ, Bryan R, et al. Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. J Clin Invest 1998; 101:2598.
- Chmiel JF, Konstan MW. Inflammation and anti-inflammatory therapies for cystic fibrosis. Clin Chest Med 2007; 28:331.
- Wheeler WB, Williams M, Matthews WJ Jr, Colten HR. Progression of cystic fibrosis lung disease as a function of serum immunoglobulin G levels: a 5-year longitudinal study. J Pediatr 1984; 104:695.
- Worlitzsch D, Tarran R, Ulrich M, et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 2002; 109:317.
- Oliver A, Cantón R, Campo P, et al. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 2000; 288:1251.
- Pier GB, Grout M, Zaidi TS, et al. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 1996; 271:64.
- Pier GB, Grout M, Zaidi TS. Cystic fibrosis transmembrane conductance regulator is an epithelial cell receptor for clearance of Pseudomonas aeruginosa from the lung. Proc Natl Acad Sci U S A 1997; 94:12088.
- Schroeder TH, Lee MM, Yacono PW, et al. CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proc Natl Acad Sci U S A 2002; 99:6907.
- 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