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Biochemistry (Cole) > Lecture 41 Collagen Structure and Function > Flashcards

Lecture 41 Collagen Structure and Function Flashcards

1
Q

Mutations in what genes account for 90% of Osteogenesis imperfecta cases?

A
  • COL1A and COL1A2
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2
Q

Is osteogeneis imperfecta a heredity disease?

A
  • Yes
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3
Q

What types of OI cases are mutations in COL1A and COL1A2 associated with and are the autosomal dominant?

A
  • I, II, III, IV

- Yes they are autosomal dominant

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4
Q

What happens with type I osteogenesis imperfecta?

A
  • you are not producing enough normal collagen
  • quantitative deficiency
  • “functional null” allele of COL1A1 gene leads to no protein being produced from one allele
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5
Q

Is the collagen formed from type I osteogenesis imperfecta normal?

A
  • yes but only half of normal amount of collagen produced
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6
Q

Is type 1 osteogenesis imperfecta autosomal dominant?

A
  • Yes, the COL1A1 or COL1A2 genes are affected
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7
Q

What are some signs/symptoms of type 1 OI?

A
  • bones predisposed to fracture
  • ## blue sclera
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8
Q

What is the mildest type of OI?

A
  • Type 1
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9
Q

What is the most severe type of OI?

A
  • Type II

- leads to death soon after birth (prenatal lethal)

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10
Q

Why do we say type II OI is autosomal dominant in THEORY?

A
  • bc it occurs mainly as spontaneous mutations due to perinatal lethality or parents turn out to be mosaic for mutation
  • there are autosomal recessive cases but these are rae
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11
Q

Why is type II OI so destructive?

A
  • mutations in the COL1A1 or COL1A2 gene produce ABNORMAL pro alpha collagen chains which become INCORPORATED into collagen trimers
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12
Q

Are there any normal collagen trimers produced with OI type II?

A
  • no because there aren’t normal pro alpha collagen chains
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13
Q

What part of the collagen trimers is most affected with OI type II?

A
  • glycine ( disrupts triple helical structure bc it cant pack tightly)
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14
Q

What are the symptoms of Type III OI?

A
  • progressive deforming type/bones fracture easily
  • short stature, spinal curvature
  • severe bone deformity
  • blue sclera
  • autosomal dominant (sometimes autosomal recessive)
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15
Q

What causes OI type III?

A
  • mutations in the COL1A1 and COL1A2 genes
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16
Q

What describes OI type IV?

A
  • severity intermediate between types 1/2
  • autosomal dominant
  • mutations primarily in COL1A2 and rarely COL1A1
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17
Q

What OI type is associates primarily with mutations in the COL1A2 gene?

A
  • Type IV OI
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18
Q

What was unique about the OI type V findings?

A
  • had an autosomal dominant inheritance pattern but parents had no mutations in collagen genes
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19
Q

What caused a suspicion of recessive forms of OI?

A
  • unaffected parents had more than one child with severe bone dysplasia
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20
Q

What is characteristic of type V OI patient?

A
  • mesh- like bone histology/calcification of radio-ulnar interosseous membrane
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21
Q

Did the new recessive forms of OI have mutations in the type I collagen genes?

A
  • nope
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22
Q

What causes the recessive OI forms?

A
  • post translational modification mutations
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23
Q

Mutations in ____ cause defective 3-prolyl-hydroxylation which delays collagen folding?

A
  • CRTAP
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24
Q

What causes type 7 OI?

A
  • hypomorphic CRTAP defect (severly reduced amounts of normal CRTAP protein)
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25
Q

What happens with a CRTAP null mutation?

A
  • results in a severe lethal form OI similar to type II
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26
Q

What is unique about the CRTAP, cylclophilin B, proly-3-hydroxylase complex?

A
  • mutations to any part of the complex will result in OI despite them have different roles
27
Q

Bottom line regarding OI causation?

A
  • OI can be causes by mutations in type I collagen genes or in genes encoding proteins involved in collagen post-translational modifications/regulation of collagen biosynthesis
28
Q

What are some of the genes encoding proteins in the collagen biosynthetic pathway linked to OI?

A
  • CRTAP
  • LEPRE
  • PPIB
  • PLOD2
  • FKBP10
  • SERPINH1
  • BMP1
29
Q

What are the symptoms of Dentinogenesis imperfecta?

A
  • hereditary of disease of dentin with
  • -> opalescent/brown teeth that wear easily
  • -> bulbous crowns
  • -> narrow roots
  • -> small/obliterated pulp chambers
  • -> frequent splitting of enamel from dentin under occlusal stress
30
Q

What type of dentinogenesis imperfecta occurs in families with OI?

A
  • type I

- (especially OI type III, IV)

31
Q

What causes Dentinogenesis imperfecta type I?

A
  • mutations in COL1A1 or COL1A2
32
Q

What is Shields Type II DI?

A
  • its not associated with OI
33
Q

What is shields type III DI?

A
  • “Brandywine type” occurs in racial segregate in maryland, U.S.A
34
Q

What causes shields type II and III DI?

A
  • mutations in DSPP`
35
Q

What are OI patients commonly treated with?

A
  • bisphosphonates (some association with osteonecrosis of the Jaw in cancer patients on high dose BPs)
36
Q

What are some implications for dental care in OI patients?

A
  • teeth are more susceptible to wear/breakage and or enamel fracturing from teeth
  • if untreated - teeth can wear down to gingiva
  • pulp chamber/ root canals may be filled with dentin, so tooth may lose feeling
37
Q

_______ is associated with abnormal collagen biosynthesis due to nutritional deficiency in Vitamin C (ascorbic acid)

A
  • scurvy
38
Q

What post translational modification is associated with scurvy?

A
  • prolyl hydroxylases and lysl hydroxylase

hydroxylates selected prolines and lysines and requires vitamin C as cofactor

39
Q

A deficiency in what vitamin leads to scurvy?

A
  • vitamin C
40
Q

What are some symptoms of scurvy?

A
  • lethargy
  • bleeding gums/mucous membranes
  • fragile blood vessels/petechial hemorrage of skin
  • loss of gingival and peridontal collagen fibers/anchoring fibers - loosing of teeth
  • bone pain
41
Q

What is an important co-factor for prolyl and lysl hydroxylases that hydroxylate proline/lysine residues?

A
  • Vitamin C
42
Q

What happens if hydroxylation is prevented?

A
  • unfolded collagen which is retained in ER and or degraded
43
Q

What does scurvy lead to?

A
  • deficient collagen assembly –> inability to renew connective tissue matrix
44
Q

What is Ehlers Danlos syndromes related to?

A
  • mutations in collagen and genes in collagen biosynthetic pathway
45
Q

Is Ehlers Danlos syndromes heterogenous?

A
  • yes
46
Q

What is Ehlers Danlos syndromes characterized by?

A
  • fragility of soft connective tissues
  • manifestations in skin, ligaments, joints, blood vessels, internal organs
  • mild skeletal abnormalities (reduced bone mass/osteopenia)
47
Q

What is the spectrum of Ehlers Danlos syndromes?

A
  • varies from mild skin + joint hyperlaxity to severe physical disability/life threatening complications such as ruptured arteries/aorta
48
Q

How many subtypes of Ehlers Danlos syndromes are recognized?

A
  • 7
49
Q

What are most Ehlers Danlos syndromes linked to?

A
  • mutations in genes encoding fibrillar collagens (esp. types III, V) or enzymes involved in post translational modifications of collagens
50
Q

If the mutation is in the gene then the disease is?

A
  • Autosomal Dominant manner
51
Q

What do the collagen fibrils in EDS look like and why?

A
  • ragged because their is a mutation in N- proteinase cleavage site in COL1A2 gene that cleaves the N terminus
52
Q

What genes are associated wtih EDS?

A
  • COL5A1
  • COL3A1
  • COL1A2
  • COL5A2
  • COL1A1
53
Q

What gene encoding proteins are associated with EDS?

A
  • PLOD1

- ADAMTS2

54
Q

What happens when type II collagen goes wrong?

A
  • chondrodysplasias
55
Q

What do all mutations causing ACGII-HCG involve?

A
  • all involve replacement of glycine by a bulkier amino acid in triple helical region of alpha 1(II) chain
56
Q

What are the results of Achondrogenesis type II/hypochondrogenesis (ACGII-HCG)?

A
  • die perinatally or in first weeks of life
  • short, barrel shaped trunk
  • very short extremities
  • large head, soft cranium
  • flat face
  • underossification of the axial skeleton
  • hypercellular epiphyseal cartilage
  • poorly organized or absent growth plate d
  • diminished extracellular matrix
  • thick, irregular collagen fibrils
57
Q

What is alport syndrome?

A
  • a mutation in collagen gene 4 leads to disruption of kidney basement membrane and causes filtration problems
58
Q

What does epidermolysis bullosa come from?

A
  • mutation in type 7 collagen
59
Q

What are the symptoms of epidermolysis bullosa?

A
  • inherited connective tissue disorder characterized by blistering of the skin and mucosal membranes due to defect in anchoring between dermis and epidermis
  • defects in enamel/caries
60
Q

What is type IV collagen important in?

A
  • important in glomerular basement membrane
61
Q

What is goodpastur syndrome?

A
  • autoimmune disease (rare)

- autoantibodies produced against non collagenous domains of type IV collagen alpha 3 chain

62
Q

What does goodpasture syndrome lead to?

A
  • leads to problems with kidney filtration, blood in urine, burning sensation when urinating, nephritis, coughing up blood, fatigue, nausea, etc. - can lead to acute renal failure
63
Q

What did Dr. Dallas find in OIM mouse?

A
  • mutation iin COL1A2 gene
  • doesn’t produce functional alpha 2 (I) collagen chains
  • makes type I collagen that is homotrimeric (composed only of alpha 1 chains)
  • leads to fractures

Biochemistry (Cole) (25 decks)

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