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INTRODUCTION

Cystic fibrosis (CF) is an inherited disease that has a high frequency in Caucasians. The disorder affects all exocrine glands, with symptoms involving the lungs and pancreas usually dominating the clinical picture. CF is challenging to diagnose and manage because of tremendous variability in the degree and pattern of involvement of organs in different persons and the burden of therapy to maintain health. This chapter focuses on the pathophysiology and management of CF. Our current understanding of the genetics and underlying molecular biology are highlighted. Recently, FDA-approved, highly effective oral CFTR modulators have become available to most patients. These new drugs have markedly improved CFTR function and clinical outcomes in most patients with severe mutations. The prognosis is improving. The majority of patients now live past the age of 18 years, and the median predicted age of survival is now in the late 40s. However, complications of the disorder due to established multiorgan disease persist and are addressed in this chapter. Finally, the approaches to develop therapies to correct mutant CFTR in those patients not responsive to the current CFTR modulators will be described.

GENETICS

CF demonstrates an autosomal-recessive pattern of inheritance. In the United States, the incidence of the disease is approximately 1 in 3000 in Caucasians, 1 in 10,000 in Hispanics, and 1 in 15,000 in African Americans,1 and the incidence is being established in patients of Asian ancestry.2 The frequency of unaffected heterozygote carriers of a CF mutation is estimated to be 1 in 26 in persons of Northern European ancestry.

CF is caused by mutations in a single gene named the cystic fibrosis transmembrane conductance regulator (CFTR). This gene was identified with an approach known as positional cloning, which permitted mapping of the gene without prior knowledge of the biochemical defect through use of polymorphic DNA markers. Following a series of molecular cloning experiments, which included “chromosome walking” and “jumping,” a candidate gene was identified. This “candidate gene” was proved to be the CF gene in 1989, largely through the discovery of a frequent mutation.3,4

The CF gene spans approximately 230 kb of DNA and contains 27 exons. The mRNA is 6.5 kb and is detected in a variety of tissues, including lungs, pancreas, and sweat glands, which are predominantly affected in pathogenesis of the disease. The deduced polypeptide was predicted to be an integral membrane glycoprotein containing 1480 amino acids (Fig. 48-1; see “Pathogenesis”). Several major and minor splicing variants in the transcripts have been described in individuals with and without CF. In most cases, however, the significance of the alternative splicing variants is not clear.

Figure 48-1

Domain model of the cystic fibrosis transmembrane conductance regulator (CFTR). Based on hydrophobicity plots, CFTR has 12 transmembrane-spanning domains, two nucleotide (N)-binding domains (NBD 1 and NBD 2), and a regulatory (R) domain. The ...

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