Modifying Factors of Cystic Fibrosis Disease: Residual Chloride Secrefion, Genefic Background and Epigenetics

Cystic fibrosis (CF) is an autosomal recessive disease caused by genetic lesions in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This CFTR gene was cloned in 1989,1-3 and located to the long arm of chromosome 7 (7q3L2). lt encodes the CFTR protein that functions as a adenosine 3',5'-cyclic monophosphate (cAMP)-regulated chloride channe1 in the apical rnembrane of exocrine epithelia, 4,5 like the sweat gland, subrnandibular glands, and the pulmonary, gastrointestinal, hepatobiliaty, and urogenital tracts. In individuals with CF the defective chloride transport leads to abnormal ion and water transport,6 whieh causes dehydration of secretions and malfunctioning of the obstructed exocrine glands, whieh typically results in chronic airway obsttuction, pancreatie insufficiency (PI), and intestinal malabsorption. The sunrival of CF patients has immensely improved throughout the last century: while in 1938, 70% of babies died within the first year of life, 7 the median survival is now reported to be towards 30 years of age,8,9 most probably due to the introduction of new therapeutic regimes, like physiotherapy, aggressive antibiotic treatment, pancreatic enzyme replacement, and proper nutrition. CF is the most common, lethal, inherited disease in the Caucasian population. lO There have been many reports on the incidence in Europe vmying from 1 in 2000 live bitths in Ireland 11 to 1 in 40000 live bit-ths in Finland. 12 In the Netherlands the incidence was estimated around 1 in 3600 life births,13 CF is found to be rare in persons from non-Caucasian origin. The most common CFTR gene mutation in the Caucasian population is the ó.F508 rnutation, a deletion of the amino acid phenylalanine at position 508, which occurs in approximately 70% of CF al1eles and 90% of CF patients. Vet, presently over 870 different CFTR mutations have been identified,14 which give rise to the cystic fibrosis phenotype.

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