ECM diseases

Question 1

What are ECM diseases due to

Answer 1

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

Question 2

What degrades elastin

Answer 2

neutrophil elastase

Question 3

what class of enzymes does elastase belong to

Answer 3

serine proteases

Question 4

What is elastase inactivated by

Answer 4

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

Question 5

What does alpha 1 antitrypsin deficiency result in

Answer 5

emphysema; not functional for oxygen exchange

Question 6

What does fibrillin mutuations cause

Answer 6

marfan syndrome;

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

Question 7

What are mutations identified with fibrillin protein

Answer 7

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

Question 8

What is Ehlers-Danlos Syndrome (EDS)

Answer 8

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

Question 9

Most forms of EDS result from defects in:

Answer 9

fibrillar collagens: I, II, III

Question 10

What is EDS type IV

Answer 10

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

Question 11

What do EDS type IV result from

Answer 11

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.

Question 12

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

Answer 12

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

Question 13

What are characteristics of osteogenesis imperfecta

Answer 13

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.

Question 14

What can lead to blue sclera?

Answer 14

osteogenesis imperfecta

Question 15

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

Answer 15

osteogenesis imperfecta

Question 16

What are two subtypes of collagen 1

Answer 16

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.

Question 17

What diseases arise if collagen isn’t cross linking

Answer 17

Weakness in blood vessels, incorrect bone formation and demineralization

• Lathyrism
• Copper deficiency

Question 18

What is lathryism

Answer 18

1. disease due to reg consumption of pea seed.

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

Question 19

lathryism is due to ________ (a nitrile)

Answer 19

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

Question 20

What does inhibition of lysyl oxidase cause

Answer 20

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.

Question 21

What does copper deficiency cause

Answer 21

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

Question 22

What is dentin sialoprotein

Answer 22

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.

Question 23

What is amelogenesis imperfecta

Answer 23

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

Question 24

collagen 4 forms:

Answer 24

network for BM

Question 25

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

Answer 25

a1 (IV); a2 (IV)

Question 26

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

Answer 26

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

Question 27

What is epidermolysis bullosa

Answer 27

Hereditary blistering diseases

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

Question 28

what is dystrophic epidermolysis bullosa

Answer 28

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

Question 29

What is recessive junctional epidermolysis bullosa

Answer 29

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

Question 30

what is recessive junctional EB Herlitz

Answer 30

1. caused by defects in laminin 5 genes

2. extensive blistering of skin and mucous membrane