ECM diseases Flashcards
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;
- long limbs
- heart defects
- vascular problems
- retinal detachment
- AD with variable expressivity
What are mutations identified with fibrillin protein
- Ca binding interactions (asp, glutamate to something else)
- disulfide sites (cysteine)
- hydrophobic packing regions
What is Ehlers-Danlos Syndrome (EDS)
- group of atleast 10 diseases
- differ clinically, biochemically, genetically
- Fragile and hyperexttensible skin
- Hypermobile joints
Most forms of EDS result from defects in:
fibrillar collagens: I, II, III
What is EDS type IV
- Most severe form (col3A1 gene)
- 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):
- Causes slow synthesis, defective secretion, inc in susceptibility to degradation
- Dominant disease due to incorporation of defective filament (molecule) into fibril
- Entire fibril defective.
What are characteristics of EDS types VIIA, B, and C
- major symptom is dislocation of major joints (hip, knees)
- skin is hyperextensible, easily bruised.
- 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
- Type C (dermatosparaxis) is autosomal recessive form resulting from deficiency of collagen N-proteinase
What are characteristics of osteogenesis imperfecta
- bone deformities
- 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
- IA- due to mutation in collagen a1 (1) gene: teeth are normal
- 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
- Lathyrism
- Copper deficiency
What is lathryism
- 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
- inherited disorder of enamel formation
- ch by hypocalcification/hypoplasia of enamel
- 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:
- other collagen a (IV( chains
- collagen VII (anchors to ECM)
- Collagen XVII (transmembrane form of collagen)
- Laminins
- 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
- casued by defects in anchoring fibrils that help attach BM to underlying stromal CT (collagen VII)
- in severe cases, fibrils are absent which leads to mutilating scarring
What is recessive junctional epidermolysis bullosa
- 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
- caused by defects in laminin 5 genes
2. extensive blistering of skin and mucous membrane
