GENOTYPE-PHENOTYPE RELATIONSHIPS IN CYSTIC FIBROSIS

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For inherited disorders, the interaction of three factors determines disease severity: (1) the nature of the defect in the responsible gene, (2) the context in which the defective gene operates (i.e., genetic background), and (3) the environmental influences. The contribution of the first component can be assessed by study of the relationship between gene defects and disease severity. Cystic fibrosis (CF) is an autosomal recessive disorder caused by abnormal function of a chloride channel called the CF transmembrane conductance regulator (CFTR). Identification of the gene encoding CFTR and the discovery of numerous mutations in this gene have provided substantial data for genotype-phenotype analysis. Insight into this relationship has also been advanced by the discovery that patients with other disorders that clinically overlap with CF have mutations in each CFTR gene. Animal studies have shown the importance of genetic background. Emerging from this mosaic is a theme common to inherited disorders: Certain aspects of the CF phenotype are primarily determined by type of CFTR mutation, whereas some features are heavily influenced by other factors.

  • 1

    CF is a variable disorder. CF is a genetic disease of epithelia that is conspicuous in the lungs; pancreas; sweat glands; and, in men, vas deferens.12, 66 The CF phenotype is highly variable among unrelated individuals and within families. Lung disease is the primary cause of death in CF, but pulmonary manifestations show a high degree of interfamilial and intrafamilial phenotypic variability. Likewise, pancreatic disease ranges from complete loss of exocrine and endocrine functions in some CF patients, to partial pancreatic function in others, to pancreatitis only in others. Sweat gland dysfunction results in increased concentrations of sodium and chloride in sweat. The level of sweat chloride varies considerably among patients: from near-normal range, 40 to 60 mM/L, to 120 mM/L, with the average level being about 100 mM/L.12, 66 Although useful for diagnostic purposes, abnormal sweat chloride concentrations do not cause illness. Male infertility is probably the most consistent feature of CF. Nearly all men with CF are infertile because of abnormalities in mesonephric duct–derived structures, the commonest of which is bilateral absence of the vas deferens.

  • 2

    Epithelial electrolyte transport is abnormal in CF. The clinical manifestations of CF are believed to be caused by abnormal electrolyte transport across epithelia leading to altered mucus viscosity and recurrent episodes of obstruction, inflammation, and progressive destruction of affected organs. For example, CF lung disease is thought to develop from the combination of absorptive and secretory defects.29, 68 Altered electrolyte composition of airway surface fluid also affects the activity of antimicrobial peptides.60 Loss of this activity has been proposed to underlie the predisposition to infection with pathogenic organisms, such as Pseudomonas aeruginosa. The importance of this pathophysiologic mechanism is unclear because precise salt concentration of airway surface fluid is a matter of some debate.29, 68 Either way, defective electrolyte transport as a result of loss of cyclic adenosine monophosphate (cAMP)–activated chloride channels and hyperactivity of sodium channels in epithelial cells is the underlying metabolic derangement in CF.65, 66

  • 3

    CFTR is defective in CF. In CF epithelia, the defect in electrolyte transport is attributed to dysfunction of the CF transmembrane conductance regulator (CFTR).52, 53 CFTR is expressed in a tissue-specific manner consistent with CF pathology.12 In airway and intestinal epithelia, CFTR is localized to the apical membrane, whereas in the sweat duct it is present in the apical and the basolateral membranes. CFTR is an important component in the coordination of electrolyte movement across membranes of epithelial cells. Human CFTR is a 1480 amino acid integral membrane protein of the adenosine triphosphate (ATP)–binding cassette family.53 CFTR is composed of two repeated motifs, each with a transmembrane domain (TMD) and a cytoplasmic nucleotide-binding fold (NBF) separated by a hydrophilic regulatory domain (R) (Fig. 1). The protein is a chloride channel activated by cAMP-mediated PKA phosphorylation of the R domain and ATP binding and hydrolysis in the NBFs.1, 20, 52 The activation and inhibition profiles of CFTR are typically used as reference points to evaluate the functional consequences of disease-associated mutations.

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    Figure 1. The cystic fibrosis transmembrane conductance regulator (CFTR). CFTR with the five domains indicated. TMD = Transmembrane domain; NBF = nucleotide binding fold; R = regulatory domain.

  • 4

    CFTR regulates separate channels in the same cell. CFTR is involved in ATP efflux and the concomitant regulation of outwardly rectified chloride channels (ORCCs).32, 33, 55, 56, 59 Activation of ORCCs contributes to the whole-cell chloride conductance in epithelial cells. ORCCs have biophysical properties distinct from CFTR. Although protein that forms ORCCs has been reconstituted in planar lipid bilayers,33 the genes encoding these channels have not been cloned. CFTR is also a regulator of the amiloride-sensitive epithelial sodium channel (ENaC).31, 62 In the absence of CFTR, ENaC is hyperactive, causing excessive absorption of sodium, increasing the difficulty of hydrating mucus secretions in the respiratory epithelia of CF patients. ENaC is composed of α, β, and γ subunits, for which the genes have been identified.4, 41

  • 5

    Mutations in CFTR cause CF. More than 800 disease-causing mutations have been identified in the CFTR gene39 (see also http://www.genet.sickkids.on.ca/cftr/). The mutation frequencies vary in relation to race and ethnicity. The common CFTR mutation ΔF508 is found on nearly 70% of CF chromosomes worldwide. An additional 20 mutations account for about 15% of CF alleles in white populations, whereas the remainder are rare mutations, occurring on only one or a few chromosomes.46 To understand the consequences of CFTR mutations, two complementary approaches have been pursued. The first method involves analysis of specific CFTR mutations to determine the functional consequences for the development of genotype-based therapies. The second approach examines the relationship between genotype and phenotype to determine the clinical implications associated with mutations in CFTR. The particular insight derived from each approach is discussed here.

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Address reprint requests to Garry R. Cutting, MD, Institute for Genetic Medicine, CMSC 9-120, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287