Describe the role of modifying genes in determining the phenotype of cystic fibrosis
? Cystic fibrosis is an autosomal recessive condition that causes premature death to sufferers.
? The primary cause of the disease is mutation in the CFTR (located at 7q31.2) gene encoding a chloride channel (ABC transporter) that locates to the plasma membrane of many cell types.
? There is considerable phenotypic variation between CF patients even where they carry the same gene mutations.
? The condition is characterised by pulmonary damage caused by the failure of normal clearance of pulmonary mucus due to its viscous nature. Other symptoms include:
o Frequent bronchial infections.
o Other tissues may be involved such as the exocrine pancreas leading to pancreatic insufficiency (PI).
o 10% of babies born with CF, suffer from bowel obstruction (meconium ileus) caused by the normal meconium being so thick that it blocks the bowel instead of passing through.
o Fertility problems result in men because of blockage of the vas deferens.
o Cystic Fibrosis can cause the blockage of small ducts in the liver in 8% of CF patients
? Even where CF individuals carry the same two copies of the mutated CFTR gene, phenotype may be very different. CF symptoms are affected by environmental and genes other than CFTR .
? Some phenotypic variation is a result of different mutations in the CFTR gene. For example the frequent ?F508 results in the protein not translocating to the plasma membrane while other mutations may have low activity but can reach the location of functional activity. Patients with homozygous ?F508 are severely affected. PI results from CF genotype.
? It has been suggested that variant forms of the following genes may modify the CF phenotype:
o Meconium ileus (MI), cystic fibrosis modifier 1 (CFM1), (chr 19) may determine MI susceptibility.
o Pulmonary TNF?, HLA, TGF?, MBL2
o Microbial infection NOS1
o GI function Muc1
? Modifying genes may be chosen as candidates (eg involved in inflammation and infection) or through linkage or association studies.
? Recent studies have provided evidence for the role of: polymorphic variants of:
o TGF? (a cytokine) in lung function with variants at -509 and codon 10 associated with better function but not with infection.
o Mannose binding lectin 2 (MBL2) (a collectin involved in innate immunity) variants with decreased production associate with infection, decreased survival and more rapid decline of lung function.
o Tumour necrosis factor alpha (TNF?) is an inflammatory cytokine and associated with lung disease. Some studies suggested variants with higher production decrease lung function but only one of these has multiple studies (-308 G>A) and no association survival, lung function or infection.
o ?1-antitrypsin is a protease inhibitor and decreased production (mutations in exon 3, 5 and 3’utr) associated with lung disease. These variants not associated with the commonly occurring phenotypes but may be involved in hepatic complications.
o GST family members are involved in detoxification reactions but two members (null mutation GSTM1 and polymorphic variants GSTP1) are not associated with CF phenotypes.
o ?-adrenergic receptor 2 not involved.
? Studies that look at gene-gene interactions or interactions of variants with environment provide some early indications of effects eg TGFb and exposure to second-hand smoke. More work required and GWA likely to provide new leads.
? Understanding the causes of phenotypic variation will assist in patient treatment regimes.
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