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Flashcards in ECM diseases Deck (30)
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1
Q

What are ECM diseases due to

A

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

2
Q

What degrades elastin

A

neutrophil elastase

3
Q

what class of enzymes does elastase belong to

A

serine proteases

4
Q

What is elastase inactivated by

A

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

5
Q

What does alpha 1 antitrypsin deficiency result in

A

emphysema; not functional for oxygen exchange

6
Q

What does fibrillin mutuations cause

A

marfan syndrome;

  1. long limbs
  2. heart defects
  3. vascular problems
  4. retinal detachment
  5. AD with variable expressivity
7
Q

What are mutations identified with fibrillin protein

A
  1. Ca binding interactions (asp, glutamate to something else)
  2. disulfide sites (cysteine)
  3. hydrophobic packing regions
8
Q

What is Ehlers-Danlos Syndrome (EDS)

A
  1. group of atleast 10 diseases
  2. differ clinically, biochemically, genetically
  3. Fragile and hyperexttensible skin
  4. Hypermobile joints
9
Q

Most forms of EDS result from defects in:

A

fibrillar collagens: I, II, III

10
Q

What is EDS type IV

A
  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
11
Q

What do EDS type IV result from

A

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.
12
Q

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

A
  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
13
Q

What are characteristics of osteogenesis imperfecta

A
  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.
14
Q

What can lead to blue sclera?

A

osteogenesis imperfecta

15
Q

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

A

osteogenesis imperfecta

16
Q

What are two subtypes of collagen 1

A
  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.
17
Q

What diseases arise if collagen isn’t cross linking

A

Weakness in blood vessels, incorrect bone formation and demineralization

  • Lathyrism
  • Copper deficiency
18
Q

What is lathryism

A
  1. disease due to reg consumption of pea seed.

2. Charac. by spine deformities, demineralization of bone, dislocation of joints, aortic aneurysms.

19
Q

lathryism is due to ________ (a nitrile)

A

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

20
Q

What does inhibition of lysyl oxidase cause

A

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.
21
Q

What does copper deficiency cause

A

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
22
Q

What is dentin sialoprotein

A

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.
23
Q

What is amelogenesis imperfecta

A
  1. inherited disorder of enamel formation
  2. ch by hypocalcification/hypoplasia of enamel
  3. enamel chips easily
24
Q

collagen 4 forms:

A

network for BM

25
Q

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

A

a1 (IV); a2 (IV)

26
Q

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

A
  1. other collagen a (IV( chains
  2. collagen VII (anchors to ECM)
  3. Collagen XVII (transmembrane form of collagen)
  4. Laminins
  5. Integrins
27
Q

What is epidermolysis bullosa

A

Hereditary blistering diseases

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

28
Q

what is dystrophic epidermolysis bullosa

A
  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
29
Q

What is recessive junctional epidermolysis bullosa

A
  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
30
Q

what is recessive junctional EB Herlitz

A
  1. caused by defects in laminin 5 genes

2. extensive blistering of skin and mucous membrane