Biochemical Basis of Disease

• Give two types of tissues that contain both elastin and fibrillin

  Aorta, skin
• Give two types of tissue that contain fibrillin but not elastin

  Eyes, muscle
• Which type of fibrillin is the most abundant in mammals?

  Fibrillin-1
• Fibrillin assembles to form beaded microfibrils in the extracellular matrix
• The mechanism by which fibrillin assembles to form microfibrils is not entirely understood
• GIve two examples of hypotheses of how fibrillin forms microfibrils

  Pleating model, staggered model
• Tropoelastin is the soluble precursor to elastin
• What unique formation property does tropoelastin have?

  Coacervation
• What is coacervation (in the context of tropoelastin)?

  Tropoelastin self-associates at increased temperatures to assemble elastin
• Which enzyme is responsible for oxidation of lysine?

  Lysyl oxidase
• What is formed when lysine is oxidised?

  allysine
• How are desmosine and isodesmosine formed?

  4 allysine residues spontaneously cross link
• What is the average length of extension for a tropoelastin molecule?

  150 nm
• What is Young's Modulus?


  Measure of elasticity, the lower the number the more elastic the thing is
• What is the main cause of death in Marfan syndrome?

  Aortic dissection
• The half-life of tropoelastin is 70 year, so the elastin you are born with lasts your whole life
• How are the elastic fibres arranged in the skin?

  Network of fibrillin microfibrils form a lattice for elastin deposition
• Ciliary zonules are composed of fibrillin molecules with no elastin
• Why do we lose ability to accomodate when focusing with age?

  Fibrillin molecules in ciliary zonules lose elasticity
• What is the prevalence of MFS?

  1 in 3000
• Give 3 common manifestations of MFS?

  Severe cardiovascular defects, ocular defects, skeletal defects
• What is the inheritance pattern of MFS?

  Autosomal dominant
• What type of skeletal manifestations occur during MFS?

  Overgrowth of long bones, tall stature, scoliosis, pectus excavatum
• Give an example of an ocular defect that occurs during MFS.

  Ectopia lentis
• What types of mutation can cause MFS?

  Premature termination codons, nonsense mutations, missense mutations
• How do missense mutations cause MFS?

  Mutations in fibrillin calcium binding domains/cysteine residues effect binding and assembly of microfibrils
• How does increase TGFb lead to aortic aneurysm + dissection?

  TGFb increases transcription of MMPs, which degrade elastin. TGFb also activates more TGFb, creating a positive feedback loop.
• How does aortic aneurysm + dissection occur?

  Aorta balloons because structure is weaker, as it balloons it becomes even weaker because it is still experiencing the same pressure -> eventually this causes a smaller tear.
• How can aortic dissection be treated if it is detected early?

  Medication for low blood pressure, aortic graft if there is a high risk of rupture
• What is LAP?

  Latency Associated Peptide (TGFB prodomain)
• In MFS mice, active TGFb levels are elevated, but there is no change in latent TGFb. This means that there is not more TGFb being produced, but more TGFb is being activated.