The nature of gene mutations, the effect of the CFTR mutation on the chloride ion channel, how cystic fibrosis affects the lungs, digestion and reproduction, and the inheritance of the condition.

What this dot point is asking

Edexcel wants you to describe the nature of gene mutations, explain how the CFTR mutation produces a faulty chloride channel, describe the effects of cystic fibrosis on the lungs, digestion and reproduction, and work out its inheritance. This dot point ties protein structure, membrane transport and genetics together, so questions often demand the whole chain from base sequence to symptom.

Gene mutations

A mutation may change one amino acid (missense), introduce a stop codon (nonsense), produce a non-functional protein, or have no effect if the change is silent because the code is degenerate. Because the genetic code is read in non-overlapping triplets, deletions and insertions of bases (unless a multiple of three) shift the reading frame, so every downstream codon is misread and the protein is usually useless.

The CFTR channel

The CFTR (cystic fibrosis transmembrane conductance regulator) protein is a channel that transports chloride ions out of epithelial cells across the cell surface membrane. The most common CFTR mutation (called delta F508) deletes three bases, removing the amino acid phenylalanine, so the channel folds incorrectly. The misfolded protein is recognised as faulty and broken down inside the cell, so few working channels reach the membrane.

The link is osmotic: normally chloride ions move out, sodium ions follow to balance charge, and the raised salt concentration in the mucus draws water out by osmosis, keeping mucus runny. Without chloride secretion, the mucus stays concentrated and viscous.

Effects on the body

• Lungs: thick mucus blocks airways, cannot be cleared easily by cilia, traps bacteria and causes repeated chest infections, inflammation and progressive lung damage. Gas exchange is reduced because the mucus increases diffusion distance.
• Digestive system: mucus blocks the pancreatic duct, so digestive enzymes (lipase, amylase, proteases) cannot reach the small intestine, reducing digestion and absorption and causing poor weight gain.
• Reproductive system: thick mucus can block the sperm ducts in males (vas deferens) and the cervix in females, reducing fertility.

Inheritance

Cystic fibrosis is autosomal recessive. A person needs two faulty alleles (genotype $ff$) to have the condition; carriers ($Ff$) have one working CFTR allele and are healthy because one normal allele makes enough functional channel. Two carrier parents ($Ff \times Ff$) have a one in four ($25\%$) chance of an affected child at each pregnancy, a one in two chance of a carrier child, and a one in four chance of an unaffected non-carrier.

Examples in context

Example 1. Liposome gene therapy trial. Because cystic fibrosis is caused by a single faulty gene with an accessible target tissue (lung epithelium), it was an early target for gene therapy. A working CFTR allele packaged in liposomes was delivered by aerosol to the airways in clinical trials. Lung function improved modestly, illustrating both the promise and the limits (the treated cells are replaced over time, so the effect is temporary). This connects directly to the gene-technology dot point.

Example 2. Why carriers persist. Roughly 1 in 25 people of European descent are CFTR carriers, far more than expected for a harmful allele. One explanation is that carriers may have had slightly better resistance to fluid loss in diseases such as cholera or typhoid, giving a heterozygote advantage that maintained the allele in the population. This links cystic fibrosis inheritance to natural selection.

Try this

Q1. Explain how a deletion mutation can affect the protein produced. [2 marks]

• Cue. It causes a frameshift, changing every codon after the deletion, so a different and usually non-functional protein is made.

Q2. Two carrier parents have a child. State the probability the child has cystic fibrosis. [1 mark]

• Cue. One in four (25 per cent), from a cross of Ff with Ff.