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Mutations in the Cystic Fibrosis Gene

Mutations in the Cystic Fibrosis Gene

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An essay for the 2011 Undergraduate Awards (Ireland) Competition by Ann-Marie Fox. Originally submitted for MH208 at NUI Maynooth, with lecturer Dr. Shirley O'Dea in the category of Medical Sciences
An essay for the 2011 Undergraduate Awards (Ireland) Competition by Ann-Marie Fox. Originally submitted for MH208 at NUI Maynooth, with lecturer Dr. Shirley O'Dea in the category of Medical Sciences

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Published by: Undergraduate Awards on Aug 31, 2012
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Mutations in the Cystic Fibrosis Gene.
Cystic fibrosis (CF) is the most common life-limiting genetic disease amongstCaucasians. It is an autosomal recessive disorder meaning just one copy of the normal CFgene makes an individual healthy. 1 in 2500 people has CF and it is reported that 1 in 25 people carry a CF-causing gene (Rawal
et al 
., 2009). CF is caused by a mutation in the
Cystic Fibrosis Transmembrane Conductance Regulator 
(CFTR) Gene which is locatedon the long arm of chromosome 7 (Rommens
et al.
, 1989). CFTR protein acts as acAMP-dependent chloride channel and is expressed on a range of cell types (Davis
et al.
,1996) including on the apical membrane of epithelial cells (Spencer & Jaffe, 2003).CFTR also has other regulatory functions including inhibition of sodium transportthrough the epithelial sodium channel, regulation of ATP channels, acidification of extracellular organelles and it is involved in bicarbonate-chloride exchange (Reisin
et al.
,1994, Stutts
et al.
, 1995, Mehta, 2005, Quinton, 2008).To date over 1500 mutations of the CFTR gene have been identified (O’Sullivan& Freedman, 2008) although most of them are rare and usually occur in conjunction withanother major mutation (Bobadilla
et al.
, 2002). F508del, also known as ΔF508 or Phe508del, is the most common mutation and it involves the deletion of 3 base pairscausing a phenylalanine residue to be deleted at codon 508 of the CFTR protein (Estivill
et al.
, 1997, Bobadilla
et al.
, 2002). This mutation accounts for about two thirds of allCFTR alleles in CF patients. The prevalence of this mutation decreases from Northwestto Southeast Europe (Morral
et al.
, 1994, Serre
et al.
, 1990). Of all the CFTR mutations,only the role of a small number is understood (O’Sullivan & Freedman, 2008). CFTR 
mutations have been grouped into five classes. In Class I mutations no functional CFTR  protein is produced due to a premature stop codon (eg. W1282X), or because of splicingdefects (eg. 1717-1G→A). Class II mutations cause misfolding of the CFTR protein. Thedysfunctional protein is bound to a chaperone protein and translocated to the endoplasmicreticulum and degraded before it reaches the apical membrane. The F508del mutation is aClass II mutation. Class III mutations disrupt the activation of CFTR by ATP or cAMPand the regulation of the protein at the plasma membrane (eg. G551D). Class IVmutations cause a reduced chloride transport though the CFTR protein at the apicalmembrane (eg. A455E). In Class V mutations, various mutations are grouped together tocause a reduction in the amount of normal CFTR protein (eg. 2789+5G→A). Thesemutations are generally associated with ‘atypical’ CF, the milder phenotype (O’Sullivan& Freedman, 2008, Spencer & Jaffe, 2003).There are numerous phenotypic features suggestive of CF. The main sign ischronic sinopulmonary disease. The lungs are continually being colonised and infected by pathogens such as
 Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilusinfluenzae
 Burkholderia cepacia
. The patient normally has chronic cough andsputum production, chest radiograph abnormalities such as bronchiectasis, airwayobstruction with wheezing and air trapping, nasal polyps and digital clubbing.Gastrointestinal and nutritional abnormalities are other hallmarks of CF. Intestinal problems such as meconium ileus occur along with pancreatic insufficiency o pancreatitis. Patients can also develop chronic hepatic disease and generally fail to thrive.Males with CF more than likely become infertile secondary to congenital bilateralabsence of the vas deferens (CBAVD) (Rosenstein & Cutting, 1998, O’Sullivan &
Freedman, 2008). However, not all men with CF are infertile. Most likely infertility isliked to specific mutations. About 2.5% of men with CF are infertile and generally carrythe 3849+10kbC→T mutation. They have no CBAVD obstruction (Stern
et al.
, 1995).The exact method of how dysfunctional CFTR leads to this fatal disease is not quite clear  but there are many proposed hypotheses.The first is the ‘Hydration Hypothesis’, also called the ‘Isosmotic VolumeHypothesis’ or the ‘Low Volume Hypothesis’. This hypothesis suggests thatdysfunctional CFTR causes loss of inhibition of sodium channels on epithelial cells.Thus, increased levels of sodium ions (Na
) and water are reabsorbed. This causes theairways to become dehydrated. The reduced concentration of chloride ions (Cl
) as aresult of dysfunctional CFTR means that the airway surface fluid (ASF) volume cannot be corrected. The lubrication between epithelium and mucous is reduced and the cilia become compressed by mucous so they can’t clear mucous and pathogens. The mucousforms plaques on the epithelium where bacteria such as
 P. aureus
can colonise.(O’Sullivan & Freedman, 2008, Chan
et al.
, 2006). The second hypothesis is the ‘SaltHypothesis’. This states that dysfunctional CFTR causes increased Na
and Cl
concentrations in the ASF. The increased NaCl concentration impairs the action of important salt-sensitive innate antibiotic molecules such as human β-defensin 1, so bacteria which are usually cleared remain in the lungs and cause infection (O’Sullivan &Freedman, 2008, Chan
et al.
, 2006). Another hypothesis suggests that with CF the hostinflammatory response does not function as it should. High numbers of inflammatorymediators are expressed by CF cell cultures. Infants with CF are quickly colonised by
S. aureus,
 P. aeruginosa
 predominates. This infection causes

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