What causes cystic fibrosis?

Cystic fibrosis (CF) is an autosomal recessive, hereditary disease, affecting 7500 people in the UK (Cystic fibrosis trust UK). The first documented case in 1936 described the condition as fibrocystatic disease of the pancreas. Before the 1960's the average life expectancy was five years; today it stands at around 31 and is expected to grow to around 40 years in the next decade as a result of advances in treatment methods. Every week five babies are born with CF and three people a week die from it usually as a result of lung damage (Cystic fibrosis trust UK). The common feature for affected systems is epithelial layers that secrete a mucus layer; including: the respiratory system, gastro-intestinal tract (including the pancreas) and the genito-urinary tract. Most complications associated with the disease arise from infection of the airways or other organs by a number of pathogenic bacteria, most notably Pseudomonas aeruginosa. Other bacteria and/or viruses may colonise mucosal surfaces and lead to infection or pave the way for more serious infections.

CF is caused by a mutation, which occurs in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The most common mutation gives rise to a protein missing amino acid 508, termed ?F508 CFTR, and accounts for around 70% of the cases reported in the UK. Patients homozygous for ?F508 generally have severe pulmonary complications and pancreatic insufficiency. Around 400 other mutations in this gene have been documented and this is most probably related to its size - 250 kbp - and large number of exons. The various phenotypes in cystic fibrosis relate to the different genotypes possible ie. the mutation may result in reduced abundance or function of CFTR within the cell or the protein could be completely absent. Due to the prevalence of the ?F508 mutation and its almost complete fatality rate, this essay will concentrate on the implications and possible solutions? to it.

In order to understand the causes of cystic fibrosis, it is necessary first to explain the way in which the normal protein works. The CFTR gene may perform a number of functions that have yet to be elucidated, but, a number have been ascertained so far, largely as a result of the cloning and sequencing of the gene itself. Now its structure is known scientists have confirmed the CFTR protein to be a channel for Cl- and HCO3- ions that is present in a number of organs.
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The wild type CFTR gene produces a molecule that becomes embedded in the cell membrane and consists of two halves forming a channel, each side having a nucleotide binding fold capable of binding ATP. In the presence of adenylate cyclase the bound ATP can be converted into cAMP. The symmetrical halves are joined by an R-domain, which is phosphorylated by protein kinases in the; when this happens a conformational change causes the pore to open as the R-domain moves away from the pore aperture. These protein kinases are activated by cAMP so when ATP and adenylate cyclase are ...

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