This is a video by Dr. Anthony Shum from an excellent series of talks by the Vera Moulton Wall Center for Pulmonary Vascular Disease (a brief summary of which is below):

Summary

  • Exome sequencing (similar to what 23andMe does) can provide insight into rare Mendelian diseases. Specifically, Dr. Shum has used this to analyze patients with autoimmune interstitial lung disease patients (typically patients who present at a young age, have pulmonary hemorrhage, arthritis, and presence of the autoantibodies ANCA and ANA) and has found that they all contain a mutation in the COPA gene, which was predicted to be damaging.
  • COPA is ubiquitously expressed, and enables protein transport between the Golgi Apparatus and the ER.
  • Mutation is specifically in WD40 region of protein, which is conserved all the way back to yeast, suggesting that this is an important region of the protein and mutations are likely to cause disease.
  • Mechanism:
    • COPA mutations present in his patients DO NOT produce haploinsufficiency.
    • COPA mutations DO NOT cause mislocalization of the COPA protein
    • COPA mutations DO cause an inability to bind di-lycine tagged proteins, and a defect in the retrograde transport proteins from the Golgi to the ER, and this causes a defect in the forward transport from the ER to the Golgi.
    • Defect in the ER/Golgi protein transport system can cause buildup of proteins within the ER and this would result physiologically in ER stress.
    • ER stress is implicated in lung disease, and in autoimmune disease.
    • ER stress is present in his patients, specifically in alveolar macrophages and in epithelium
    • B Cells from his patients are more susceptible to ER stress when exposed to ER stress inducers, compared to cells from healthy patients
    • When mutant COPA is transfected into healthy cells, an increase in ER stress is observed
    • The link between ER stress and patient phenotype of lung autoimmunity: in the presence of ER stress, Th-17 priming cytokines are upregulated in antigen-presenting cells with mutations in COPA gene. And finally, his patients have a significant increase in Th-17 polarized cells.
    • Thus, mutations in WD40 COPA can cause autoimmune associated lung and joint disease.

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