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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
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Layers of skin (from top to bottom)
- Epidermis, includes:
- Stratum corneum
- Stratum granulosum (granular layer)
- Stratum spinosum (spinous layer)
- Basal layer
- Basal lamina
- Dermis
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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
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Mutations in K5/K14 cause ______
EBS
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EBS is caused by mutations in _______
K5/K14
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K5 and K14 are found ______
Basal layer cells
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EBS is normally (dominant/recessive). Why?
- Dominant
- Having one bad copy of either K5 or K14 causes bad K5/K14 heterodimers to form
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Keratin dimer structure
- Obligate heterodimers
- One basic (K1-K8, larger), one acidic (K10-K19, smaller)
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K1 and K10 are found in ______
epidermal suprabasal cells
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Mutation in K1 or K10 causes _______
Epidermolysis Hyperkeratosis
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Epidermolysis Hyperkeratosis is caused by mutations in ________
K1, K10
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Why do keratotic plaques form in EH?
Damage is above mitotically proliferative basal layer, so basal cells proliferate rapidly to compensate
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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
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K9 mutations cause ______
palmoplantar keratoderma
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Palmoplantar keratoderma is caused by mutations in ________
K9
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K6/16/17 mutations cause _______
pachyonychia congenita
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Pachyonychia congenita is caused by mutations in ______
K6/16/17
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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
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JEB + muscular dystrophy is caused by mutations in _______
plectin
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Generalized atrophic benign EB (GABEB) caused by mutation in _______
BPAG-2
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JEB + pyloric atresia caused by mutation in _______
Integrin a6b4
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Classical JEB caused by mutation in ______
Laminin V
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JEB mode of inheritance
autosomal recessive ALWAYS
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EBS mode of inheritance
USUALLY autosomal dominant
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DEB caused by lack of _______
collagen VII
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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)
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Severe scarring in EB occurs when blisters are above or below what point?
Below basal lamina
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DEB patients have increased risk for what?
SCC
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DEB mode of inheritance
Autosomal recessive and autosomal dominant
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Lab test to diagnose EB and what type of EB?
Direct Immunofluorescence (DIF)
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Bullous pemphigoid
Autoimmune disorder where autoantibodies bind to BPAG1
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Cicatricial pemphigoid
Autoimmune disorder with autoantibodies to laminin V
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Pemphigus foliaceous
Autoimmune disorder, attacks desmoglein 1
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Pemphigus vulgaris
Autoimmune; attacks desmoglein 3
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EB acquisita
Autoimmune; attacks collagen VII
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______ are excellent tumor identification markers
Antibodies to intermediate filaments
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How many types of keratins?
54
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