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Pathophysiology


Table 1: Mutations in the CFTR gene and their pathophysiological consequences Class


Normal Molecular defect No defect


Representative mutations


Phenotype I No synthesis


G542X, W1282X, R553X


Severe, pancreatic insufficient


II


Misfolding, degradation


F508del, 11507, S549R, S945D


Severe, pancreatic insufficient


III


Defective regulation


G551D, S492F, V520F, R553G


Severe IV


Impaired channel function


R117H, G85E, R347P, R334W


Mild, pancreatic sufficient


V


Reduced channel density


1811+16kb a > g, 3849 + 10kb


Mild, pancreatic sufficient


VI


Decreased membrane stability


L1389X, 4279insA


Mild, pancreatic sufficient


cAMP activated Cl– only conducts Cl–


channel.8


CFTR not ions but also anions


such as HCO3 , ATP and glutathione.9–11 –


CFTR is believed to interact with several other intracellular and transmembraneous proteins.12


However


it is not absolutely clear to what extent these interactions, or the lack thereof, impact on the functions of cells expressing CFTR. To date, almost 2000 different mutations in the CFTR gene have been reported and most of these mutations have been classified as five different types (Table 1).


A majority of CF patients carry, at least on one allele, a mutation that leads to deletion of a phenylalanine in position 508 of the protein (F508del). The mutated protein is improperly folded and degraded within the ubiquitin pathway.13


Mutations that prevent


proper delivery of the protein are usually denoted as class II mutations. More than 70% of all CF patients are homozygous for the F508del mutation and more than 90% of all patients carry that mutation on at least one allele. Another class of mutations introduces a stop codon in the genetic sequence that results in the complete absence of any channel protein (class I mutations). Some studies have tried to find a genotype–phenotype correlation.14,15


To this end, none of these


studies have succeeded in demonstrating a clear correlation. This might, in part, be due to the strong impact that environmental and social factors have on the disease. Most recently a variety of ‘modifier genes’ are thought to influence the outcome of the disease.14 Despite the abundant analyses by geneticists, most clinicians prefer a somewhat simpler classification by considering patients with pancreatic insufficiency as severe cases, compared with those who retain pancreatic function as mild cases.


What is the real defect? After the cloning of the gene encoding


for CFTR in 1989,16 the scientific


community was full of optimism that CF as a fatal disease could be cured within a decade. In fact, the scientific efforts undertaken to understand the complex nature of CFTR and the consequences of CFTR mutations on the human physiology had been unprecedented. Nevertheless, while the molecular functions of the protein are somewhat understood, it is difficult to explain the pathophysiology of CF patients by a


The only explanation for this phenomenon was that the fractional Na+ conductance was elevated. Because no abnormality in the structure and subunit composition of eNaC in CF was reported, the apparent increase in Na+


rather scant (surface epithelium). Measurements of the transepithelial voltage difference across nasal mucosae revealed a substantially increased voltage in CF patients compared with normal.20


transport remains puzzling. Some studies have


"Most CF patients carry, at least on one allele, a mutation that leads to deletion of a phenylalanine in position 508 of the protein"


mere lack of electrolyte transport. The majority of scientists favour as explanation an imbalance between electrolyte absorption and secretion that results in an impaired hydration of the epithelial surface liquid. Cellular models have supported this hypothesis, while transgenic animal models in which the CF-causing mutations have been introduced did not reproduce the expected phenotype. A transgenic mouse in which the beta subunit of the epithelial Cl–


channel is overexpressed is


currently the best model for CF-like lung disease in rodents despite the fact that the CFTR protein is functioning properly.17


Transgenic pig models


bearing CFTR mutations that lead to problems in the GI tract and which have a higher likelihood of developing lung disease than a normal litter have also been developed.18,19


CFTR in the lung


Airway epithelia can be divided in two different functional entities: primarily absorptive and secretory cells. The absorptive surface epithelia of the airways express high levels of the epithelial sodium channel, eNaC, whereas the CFTR expression pattern is


proposed that activation of CFTR leads to an apparent downregulation of eNaC activity that is absent when CFTR is mutated.21


A study published in 1996 proposed a new explanation for the pathophysiology in the airways of CF patients.22


The


investigators added bacteria to cultured airway epithelial cells collected either from CF patients or normal specimens and grown on an air–liquid interface. Their striking observation was that the growth rate in the presence of CF cells was relatively high compared with normal cells. When the culture media of the CF cells was diluted, the growth rate was identical in the two groups. Analysis of surface liquid samples obtained from CF patients and normals suggested that the NaCl content in CF lungs was increased. The authors proposed that the altered composition of the surface liquid produced by CF cells would result in a decreased first-strike capacity of antimicrobial peptides secreted on the surface of the cells. These peptides, beta-defensins,23


were inactive when the


ionic strength of the surrounding liquid exceeded plasma levels. The implications of these observations led to an ongoing discussion between competing labs


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