Cystic fibrosis - just one small change in a protein

Cystic Fibrosis

• Caused by a mutation of the Cystic Fibrosis Transmembrane Regulator (CFTR) gene
  • Covered in Unit 2 Section 3.2.1
• CFTR is a plasma membrane protein
  • Normally, it transports chloride ions out of the cell by active transport
  • In cystic fibrosis, a mutation alters the tertiary structure of CFTR
  • The protein fails to reach plasma membrane
  • Accumulation of Cl- and Na+ (attracted by negative Cl-) within the cell
  • Secretions are thick as water stays inside the cell due to high internal Na+ (altered water potential)
  • NB: water always follows Na+
• Lungs
  • "Produce less mucus than normal "1
  • Lung surface is dehydrated and mucus adheres to airways
  • This favours the growth of bacteria causing chronic infection
  • White cells engulf bacteria and die (phagocytosis)
  • The DNA from dead inflammatory cells (pus) contributes to thick sputum
  • Sputum has an increased viscosity and cannot be removed by the ciliary escalator
  • Obstructs airways and causes further inflammation
• Pancreas
  • Thick digestive juice blocks passage from pancreas into small intestine (duodenum)
  • Obstruction may cause chronic inflammation of the pancreas
  • Pancreas fails to secrete digestive enzymes
  • Food is not broken down and not absorbed
• Sweat
  • CFTR works differently in the skin
  • Normally, chloride are transferred from the sweat into the cell
  • Excessive NaCl remains on the skin - sweat taste saltier than normal
  • Sweat can be collected and analysed to diagnose CF
• Slow growth
  • Less efficient energy/fooduptake due to malabsorption
  • High energy consumption due to chronic inflammation of the lungs
  • To compensate, children require high calorie diet (chocolate, crisps)
• Treatment
  • Pancreatic enzyme replacement therapy (PERT) to treat fat malabsorption
  • Fat-soluble vitamin supplements (A, E, D, K) to prevent deficiencies
  • Inhaled enzyme DNAse breaks down excessive DNA and thin mucus
  • Antibiotics to treat lung infections (frequent use causes antibiotics resistance)

References

• 1) Henke MO, Renner A, Huber RM, Seeds MC, Rubin BK. MUC5AC and MUC5B Mucins Are Decreased in Cystic Fibrosis Airway Secretions. Am J Respir Cell Mol Biol. 2004 Jul;31(1):86-91. Epub 2004 Feb 26.