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The genetics of cystic fibrosis lung disease

Since the isolation of the gene responsible for cystic fibrosis in 1989 we have witnessed rapid progress in our understanding of this common genetic disorder. Progressively more detailed knowledge of the disease causing mutations, the gene expression patterns, the protein structure, and its function as an ion channel has allowed the development of reliable screening programmes, the creation of animal models, and the design of novel therapeutic approaches. The biological basis of many aspects of the disease phenotype are becoming clearer, including recent significant advances in understanding the pathogenesis of the characteristic and ultimately fatal lung disease. While this great expansion of knowledge has started to bridge the gap between our understanding of the genetic defect and the well documented clinical sequelae, it has also served to demonstrate the mechanistic complexity of this “simple” single gene defect.

Cystic fibrosis is the most common lethal autosomal recessive genetic disorder in Caucasian populations with a carrier frequency of one in 25. It affects about one in 2500 live births and has a median life expectancy of 28 years.1 

The characteristic manifestations are due primarily to dysfunction of exocrine glands, producing viscid, dehydrated secretions. The resultant phenotype is of salty sweat, pancreatic insufficiency (with consequent malabsorption and failure to thrive), intestinal obstruction (with meconium ileus in 10–20% of patients in the first few days of life), infertility and severe pulmonary disease. The electrophysiological profile of affected tissues shows characteristic abnormalities in the transport of chloride and sodium ions across the apical membrane.2 

The recent advancement of our knowledge was sparked by the cloning, in 1989, of the gene responsible for the disease—the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. Located on the long arm of human chromosome 7, it spans over 250 kb, contains 27 exons, and encodes a 1480 residue …