CFM 2: Epidermolysis Bullosa Case

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  1. Structure of intermediate filament
    • Central rod domain (highly conserved) with 4 helical domains; flanked by head and tail sequences
    • Form coiled coil parallel dimers
    • Dimers then form antiparallel staggered tetramers
    • Tetramers elongate to form protofilaments
    • Two protofilaments coil around each other forming a protofibril
    • Four protofibrils align in a staggered array to form the intermediate filament
    • Total of 32 polypeptides
  2. Layers of skin (from top to bottom)
    • Epidermis, includes:
    •      Stratum corneum
    •      Stratum granulosum (granular layer)
    •      Stratum spinosum (spinous layer)
    •      Basal layer
    • Basal lamina
    • Dermis
  3. 3 general types of EB and which layer the blisters occur
    • EB simplex: basal layer (just above basal lamina)
    • Junctional EB: basal lamina
    • Dystrophic EB: dermis
  4. Mutations in K5/K14 cause ______
  5. EBS is caused by mutations in _______
  6. K5 and K14 are found ______
    Basal layer cells
  7. EBS is normally (dominant/recessive). Why?
    • Dominant
    • Having one bad copy of either K5 or K14 causes bad K5/K14 heterodimers to form
  8. Keratin dimer structure
    • Obligate heterodimers
    • One basic (K1-K8, larger), one acidic (K10-K19, smaller)
  9. K1 and K10 are found in ______
    epidermal suprabasal cells
  10. Mutation in K1 or K10 causes _______
    Epidermolysis Hyperkeratosis
  11. Epidermolysis Hyperkeratosis is caused by mutations in ________
    K1, K10
  12. Why do keratotic plaques form in EH?
    Damage is above mitotically proliferative basal layer, so basal cells proliferate rapidly to compensate
  13. Systematized Epidermal Nevus
    • Mosaic form of EH (i.e. some cells have EH problem, some don't)
    • Occurs due to post-zygotic mutations, resulting in one population of normal cells and one population of mutant cells
    • May be germ line mosaic, so full blown EH can be transmitted to children
  14. K9 mutations cause ______
    palmoplantar keratoderma
  15. Palmoplantar keratoderma is caused by mutations in ________
  16. K6/16/17 mutations cause _______
    pachyonychia congenita
  17. Pachyonychia congenita is caused by mutations in ______
  18. Structure of hemidesmosome, from basal cell to dermis, including the proteins involved in each
    • Keratin filaments: K5/14
    • Intracellular plaque: Plectin, BPAG-1
    • Transmembrane proteins: Integrin a6B4, BPAG-2
    • Lamina Lucida: Laminin V
    • Lamina densa: Collagen IV, Laminin I
    • Anchoring Fibrils: Collagen VII
    • Anchoring Plaques: Collagen IV
  19. JEB + muscular dystrophy is caused by mutations in _______
  20. Generalized atrophic benign EB (GABEB) caused by mutation in _______
  21. JEB + pyloric atresia caused by mutation in _______
    Integrin a6b4
  22. Classical JEB caused by mutation in ______
    Laminin V
  23. JEB mode of inheritance
    autosomal recessive ALWAYS
  24. EBS mode of inheritance
    USUALLY autosomal dominant
  25. DEB caused by lack of _______
    collagen VII
  26. How is collagen VII assembled into fibrils?
    • Triple helical assembly with non-collagenous head and tail
    • Two tails line up, tails break up
    • So, bivalent structure (head on each side)
  27. Severe scarring in EB occurs when blisters are above or below what point?
    Below basal lamina
  28. DEB patients have increased risk for what?
  29. DEB mode of inheritance
    Autosomal recessive and autosomal dominant
  30. Lab test to diagnose EB and what type of EB?
    Direct Immunofluorescence (DIF)
  31. Bullous pemphigoid
    Autoimmune disorder where autoantibodies bind to BPAG1
  32. Cicatricial pemphigoid
    Autoimmune disorder with autoantibodies to laminin V
  33. Pemphigus foliaceous
    Autoimmune disorder, attacks desmoglein 1
  34. Pemphigus vulgaris
    Autoimmune; attacks desmoglein 3
  35. EB acquisita
    Autoimmune; attacks collagen VII
  36. ______ are excellent tumor identification markers
    Antibodies to intermediate filaments
  37. How many types of keratins?
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CFM 2: Epidermolysis Bullosa Case
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