Lecture 41 Collagen Structure and Function Flashcards
1
Q
Mutations in what genes account for 90% of Osteogenesis imperfecta cases?
A
- COL1A and COL1A2
2
Q
Is osteogeneis imperfecta a heredity disease?
A
- Yes
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
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
5
Q
Is the collagen formed from type I osteogenesis imperfecta normal?
A
- yes but only half of normal amount of collagen produced
6
Q
Is type 1 osteogenesis imperfecta autosomal dominant?
A
- Yes, the COL1A1 or COL1A2 genes are affected
7
Q
What are some signs/symptoms of type 1 OI?
A
- bones predisposed to fracture
- ## blue sclera
8
Q
What is the mildest type of OI?
A
- Type 1
9
Q
What is the most severe type of OI?
A
- Type II
- leads to death soon after birth (prenatal lethal)
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
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
12
Q
Are there any normal collagen trimers produced with OI type II?
A
- no because there aren’t normal pro alpha collagen chains
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)
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)
15
Q
What causes OI type III?
A
- mutations in the COL1A1 and COL1A2 genes
16
Q
What describes OI type IV?
A
- severity intermediate between types 1/2
- autosomal dominant
- mutations primarily in COL1A2 and rarely COL1A1
17
Q
What OI type is associates primarily with mutations in the COL1A2 gene?
A
- Type IV OI
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
19
Q
What caused a suspicion of recessive forms of OI?
A
- unaffected parents had more than one child with severe bone dysplasia
20
Q
What is characteristic of type V OI patient?
A
- mesh- like bone histology/calcification of radio-ulnar interosseous membrane
21
Q
Did the new recessive forms of OI have mutations in the type I collagen genes?
A
- nope
22
Q
What causes the recessive OI forms?
A
- post translational modification mutations
23
Q
Mutations in ____ cause defective 3-prolyl-hydroxylation which delays collagen folding?
A
- CRTAP
24
Q
What causes type 7 OI?
A
- hypomorphic CRTAP defect (severly reduced amounts of normal CRTAP protein)
25
What happens with a CRTAP null mutation?
- results in a severe lethal form OI similar to type II
26
What is unique about the CRTAP, cylclophilin B, proly-3-hydroxylase complex?
- mutations to any part of the complex will result in OI despite them have different roles
27
Bottom line regarding OI causation?
- 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
What are some of the genes encoding proteins in the collagen biosynthetic pathway linked to OI?
- CRTAP
- LEPRE
- PPIB
- PLOD2
- FKBP10
- SERPINH1
- BMP1
29
What are the symptoms of Dentinogenesis imperfecta?
- 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
What type of dentinogenesis imperfecta occurs in families with OI?
- type I
| - (especially OI type III, IV)
31
What causes Dentinogenesis imperfecta type I?
- mutations in COL1A1 or COL1A2
32
What is Shields Type II DI?
- its not associated with OI
33
What is shields type III DI?
- "Brandywine type" occurs in racial segregate in maryland, U.S.A
34
What causes shields type II and III DI?
- mutations in DSPP`
35
What are OI patients commonly treated with?
- bisphosphonates (some association with osteonecrosis of the Jaw in cancer patients on high dose BPs)
36
What are some implications for dental care in OI patients?
- 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
_______ is associated with abnormal collagen biosynthesis due to nutritional deficiency in Vitamin C (ascorbic acid)
- scurvy
38
What post translational modification is associated with scurvy?
- prolyl hydroxylases and lysl hydroxylase
| hydroxylates selected prolines and lysines and requires vitamin C as cofactor
39
A deficiency in what vitamin leads to scurvy?
- vitamin C
40
What are some symptoms of scurvy?
- 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
What is an important co-factor for prolyl and lysl hydroxylases that hydroxylate proline/lysine residues?
- Vitamin C
42
What happens if hydroxylation is prevented?
- unfolded collagen which is retained in ER and or degraded
43
What does scurvy lead to?
- deficient collagen assembly --> inability to renew connective tissue matrix
44
What is Ehlers Danlos syndromes related to?
- mutations in collagen and genes in collagen biosynthetic pathway
45
Is Ehlers Danlos syndromes heterogenous?
- yes
46
What is Ehlers Danlos syndromes characterized by?
- fragility of soft connective tissues
- manifestations in skin, ligaments, joints, blood vessels, internal organs
- mild skeletal abnormalities (reduced bone mass/osteopenia)
47
What is the spectrum of Ehlers Danlos syndromes?
- varies from mild skin + joint hyperlaxity to severe physical disability/life threatening complications such as ruptured arteries/aorta
48
How many subtypes of Ehlers Danlos syndromes are recognized?
- 7
49
What are most Ehlers Danlos syndromes linked to?
- mutations in genes encoding fibrillar collagens (esp. types III, V) or enzymes involved in post translational modifications of collagens
50
If the mutation is in the gene then the disease is?
- Autosomal Dominant manner
51
What do the collagen fibrils in EDS look like and why?
- ragged because their is a mutation in N- proteinase cleavage site in COL1A2 gene that cleaves the N terminus
52
What genes are associated wtih EDS?
- COL5A1
- COL3A1
- COL1A2
- COL5A2
- COL1A1
53
What gene encoding proteins are associated with EDS?
- PLOD1
| - ADAMTS2
54
What happens when type II collagen goes wrong?
- chondrodysplasias
55
What do all mutations causing ACGII-HCG involve?
- all involve replacement of glycine by a bulkier amino acid in triple helical region of alpha 1(II) chain
56
What are the results of Achondrogenesis type II/hypochondrogenesis (ACGII-HCG)?
- 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
What is alport syndrome?
- a mutation in collagen gene 4 leads to disruption of kidney basement membrane and causes filtration problems
58
What does epidermolysis bullosa come from?
- mutation in type 7 collagen
59
What are the symptoms of epidermolysis bullosa?
- 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
What is type IV collagen important in?
- important in glomerular basement membrane
61
What is goodpastur syndrome?
- autoimmune disease (rare)
| - autoantibodies produced against non collagenous domains of type IV collagen alpha 3 chain
62
What does goodpasture syndrome lead to?
- 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
What did Dr. Dallas find in OIM mouse?
- 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
