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CFTR Expression and Organ Damage in Cystic Fibrosis

Eduardo F. Tizzano; and Manuel Buchwald
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From Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, and the Hospital for Sick Children, Toronto, Ontario, Canada. Requests for Reprints: Manuel Buchwald, PhD, Department of Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8 Canada. Acknowledgments: The authors thank Peter Durie and Sylvia Gartner for their helpful comments on the manuscript. Grant Support: In part by grants from Institut de Recerca Hospital de Sant Pau, the Canadian Cystic Fibrosis Foundation, and Inspiraplex.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;123(4):305-308. doi:10.7326/0003-4819-123-4-199508150-00009
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The cloning of the defective gene in cystic fibrosis (CFTR) is the most important step to date toward understanding the pathogenesis of the disease and developing novel therapeutic strategies.Although many studies have provided insights into the molecular defects and knowledge of the expression and role of the gene, the basic defect and its pathogenesis are still unclear. We hypothesize that organ damage in cystic fibrosis is the result of a combination of at least three main factors: the genotype (the type of mutation that alters the function of the cystic fibrosis transmembrane regulator [CFTR]), the rate of CFTR-mediated chloride secretion in the epithelium of each organ (inferred from the level of expression of the gene), and the anatomical and physiologic characteristics of the affected organs (the size and contents of the ducts). Confirmation of this hypothesis should allow a better understanding of the pathogenesis of the disease and help prevent organ damage.


Grahic Jump Location
Figure 1.
Flow chart describing the three factors that lead to organ damage in cystic fibrosis: the genotype, the secretion of cystic fibrosis transmembrane regulator (CFTR), and the intrinsic properties of the affected organs.

Several additional factors influence the final phenotype. In the case of pancreatic disease, a clear correlation has been shown between genotype and phenotype, with a specific set of mutations (for example, R117H) leading to pancreatic sufficiency and the rest, including DF508, to pancreatic insufficiency. Male duct disease is the paradigmatic finding in male patients with cystic fibrosis, suggesting that male duct abnormalities are present regardless of the type of mutation. Intestine and liver disease are probably influenced by other genetic and environmental factors, as evidenced by the lower prevalence of meconium ileus in newborns compared with fetuses. The lung, protected by unknown factors during intrauterine development, is strongly influenced by respiratory pathogens and the host inflammatory response after birth.

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