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Flashcards in ECM diseases Deck (30):

What are ECM diseases due to

hereditary; most defects are in collagen genes or can be due to toxins or dietary deficiencies


What degrades elastin

neutrophil elastase


what class of enzymes does elastase belong to

serine proteases


What is elastase inactivated by

alpha 1- antitrypsin aka serpin; it protects tissues from released ser proteases and is known as a suicide inhibitor


What does alpha 1 antitrypsin deficiency result in

emphysema; not functional for oxygen exchange


What does fibrillin mutuations cause

marfan syndrome;
1. long limbs
2. heart defects
3. vascular problems
4. retinal detachment
5. AD with variable expressivity


What are mutations identified with fibrillin protein

1. Ca binding interactions (asp, glutamate to something else)
2. disulfide sites (cysteine)
3. hydrophobic packing regions


What is Ehlers-Danlos Syndrome (EDS)

1. group of atleast 10 diseases
2. differ clinically, biochemically, genetically
3. Fragile and hyperexttensible skin
4. Hypermobile joints


Most forms of EDS result from defects in:

fibrillar collagens: I, II, III


What is EDS type IV

1. Most severe form (col3A1 gene)
2. Autosomal dominant that leads to:
-arterial rupture (sudden death)
-intestinal perforation
-rupture of uterus during pregnancy or labor
-easily bruised thin, translucent skin


What do EDS type IV result from

Mutations in collagen alpha 1 (III):
1. Causes slow synthesis, defective secretion, inc in susceptibility to degradation
2. Dominant disease due to incorporation of defective filament (molecule) into fibril
3. Entire fibril defective.


What are characteristics of EDS types VIIA, B, and C

1. major symptom is dislocation of major joints (hip, knees)
2. skin is hyperextensible, easily bruised.
3. Types A and B result from mutations in collagen a1(1) or a2(I) gene that eliminate cleavage site for collagen N-proteinase; incompletely processes collagens assemble to form defective fibrils
4. Type C (dermatosparaxis) is autosomal recessive form resulting from deficiency of collagen N-proteinase


What are characteristics of osteogenesis imperfecta

1. bone deformities
2. variants result from mutations producing shortened collagen a(1) chains, which causes short deletion of a coding region:
-defective chains assemble to form defective helix, then into fibrils, fibers
-Defective collagens are rapidly degraded
-Leads to weakened fibers, weak CT, massive reduction in bone mass.


What can lead to blue sclera?

osteogenesis imperfecta


What is the most common collagen mutation that has an effect on teeth

osteogenesis imperfecta


What are two subtypes of collagen 1

1. IA- due to mutation in collagen a1 (1) gene: teeth are normal
2. IB- due to mutation in collagen a2 (1) gene: dentinogenesis imperfecta; teeth opalascent and blue or brown.


What diseases arise if collagen isn't cross linking

Weakness in blood vessels, incorrect bone formation and demineralization
-Copper deficiency


What is lathryism

1. disease due to reg consumption of pea seed.
2. Charac. by spine deformities, demineralization of bone, dislocation of joints, aortic aneurysms.


lathryism is due to ________ (a nitrile)

beta-aminopropionitrile; potent irreversible inhibitor of extracellular enzyme lysyl oxidase.


What does inhibition of lysyl oxidase cause

blocks collagen cross linking, reduces fibril stability:
-during collagen biosynthesis, lysyl hydroxylase in ER converts some lysines at Y position to Gly-X-Y repeats to hydroxylysines
-Outside of cell, lysyl oxidase converts some hyroxylysines to aldehyde derivatives, which get cross linked to other lysines in other chains.


What does copper deficiency cause

Affects cross linking; lysyl oxidase requires copper ion as a cofactor
-primarily affects skin (becomes loose and wrinkled)
-Two rare X-linked diseases cause defects in copper metabolism


What is dentin sialoprotein

implicated as defective gene in dentinogenesis imperfecta type II.
-inherited disorder ch by irregular dentin formation in both primary and secondary dentition
-teeth are blue, gray or voilet
-leads to severe damage and erosion of teeth.


What is amelogenesis imperfecta

1. inherited disorder of enamel formation
2. ch by hypocalcification/hypoplasia of enamel
3. enamel chips easily


collagen 4 forms:

network for BM


No mutations in collagen _____ or ____ genes arise when there are defects in BM

a1 (IV); a2 (IV)


Defects in genes assoc with inherited diseases that affect BM include:

1. other collagen a (IV( chains
2. collagen VII (anchors to ECM)
3. Collagen XVII (transmembrane form of collagen)
4. Laminins
5. Integrins


What is epidermolysis bullosa

Hereditary blistering diseases
-Deep sep below BM can lead to scarring that in severe cases can lead to loss of function.


what is dystrophic epidermolysis bullosa

1. casued by defects in anchoring fibrils that help attach BM to underlying stromal CT (collagen VII)
2. in severe cases, fibrils are absent which leads to mutilating scarring


What is recessive junctional epidermolysis bullosa

1. caused by defects in collagen alpha 1 (XVII)
-leads to sep within skin BM
-non scarring blistering
-dental caries due to enamel hypoplasia and tooth pitting
-failure of teeth to erupt


what is recessive junctional EB Herlitz

1. caused by defects in laminin 5 genes
2. extensive blistering of skin and mucous membrane