Since the CFTR gene was cloned in 1989, more than 1800 disease-causing mutations have been identified. They can be classified on the basis of clinical course of CF or the nature of the underlying defect. Mechanistically, they may result in reduced quantity of  functional CFTR that reaches the cell surface or reduced function of CFTR that reaches the cell surface. As we shall see these differences impact on the development of treatment strategies. They can also be classified as severe or mild, depending on the clinical phenotype. Severe mutations are associated with complete loss of CFTR protein function, whereas mild mutations allow some residual function. The most common severe CFTR mutation is a deletion of three nucleotides coding for phenylalanine at amino acid position 508 (ΔF508). This causes misfolding and total loss of the CFTR. Worldwide, ΔF508 mutation is found in approximately 70% of patients with CF. Since CF is an autosomal recessive disease, affected persons harbor mutations on both alleles. As discussed later, the nature of mutations on the two alleles influences the overall phenotype, as well as organ-specific manifestations. Although CF remains one of the best-known examples of the “one gene–one disease” axiom, there is increasing evidence that other genes modify the frequency and severity of organ-specific manifestations. Examples of modifier genes include mannose-binding lectin 2 (MBL2) and transforming growth factor-β1 (TGFβ1). It is postulated that polymorphisms in these genes influence the ability of the lungs to tolerate infections with virulent microbes (see later), thus modifying the natural history of CF.
Fig. 7.4 ). Pancreatic abnormalities are present in 85% to 90% of patients. In the milder cases, there may be only accumulations of mucus in the small ducts, with some dilation of the exocrine glands. In more advanced cases, usually seen in older children or adolescents, the ducts are totally plugged, causing atrophy of the
Fig. 7.5 ). The total loss lead to vitamin A deficiency. This may contribute to squamous metaplasia of the lining epithelium of the pancreatic ducts, which tions. Thick viscid plugs of mucus also may be found in the small
Azoospermia Infertility Bilateral obstruction of vas deferens
Fig. 7.4 Tissues affected in patients with CF. (Adapted from Cutting GR: Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet 16:45, 2015.) intestine of infants. Sometimes these cause small bowel obstruction, known as meconium ileus.
Fig. 7.6). These changes stem from obstruc tion of the air passages by the viscous mucus secretions of submucosal glands and superimposed infections. The bronchioles often are distended with thick mucus, associated with marked hyperplasia and hypertrophy of the mucus-secreting cells. Superimposed infections give rise to severe chronic bronchitis and