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Applied Biochemistry > Collagen Structure and Function Part 2 > Flashcards

Collagen Structure and Function Part 2 Flashcards

1
Q

osteogenesis imperfecta is a — disease

A

hereditary

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2
Q

osteogenesis imperfecta

A

bones are extremely brittle and break, often for little or no apparent cause

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3
Q

how many people does OI affect in the US?

A

20,000-50,000

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4
Q 
Mutations in (2) genes account
for ~90% of OI cases (>150 different mutations
identified)
A

COL1A1 and COL1A2

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5
Q

COL1A1 and COL1A2 mutations associated with the four types of OI defined classically

A

types I, II, III, IV

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6
Q

OI is mostly – –

A

autosomal dominant

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7
Q

Classical Osteogenesis Imperfecta is due to (2) Abnormalities of Type I Collagen

A

quantitative

qualitative

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8
Q

most common/mild type of OI

A

type 1

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9
Q

in type 1, bones are predisposed to

A

fracture (most occur before puberty)

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10
Q

symptoms of type 1 OI

A

normal stature/blue sclera

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11
Q

type 1 OI is

A

autosomal dominant

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12
Q

in most cases, “functional null” allele of COL1A1 or COL1A2 genes leads to

A

no protein being produced from one allele

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13
Q

other allele unaffected therefore patients make

A

REDUCED amounts of

NORMAL collagen I

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14
Q

mutations can be;

A

allelic deletion, promoter/enhancer mutations,
splicing mutations, premature termination – i.e. mutations which result
in reduced (or no) production of alpha collagen I chains or production
of alpha collagen I chains that are degraded or incapable of being
assembled into trimers

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15
Q

trimers are formed normally (encoded by normal allele), but

A

only half the normal amount of collagen produced (quantitative deficiency)

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16
Q

normal protein being made but in reduced amounts is known as

A

quantitative deficiency

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17
Q

most severe form of OI

A

type 2 (perinatal lethal)

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18
Q

symptoms of type 2 OI (2)

A

numerous fractures and severe bone deformity

short stature

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19
Q

type 2 OI is

A 
autosomal dominant (but occurs mainly as spontaneous mutations due to perinatal lethality or parents turn out to be mosaic for mutation)
autosomal recessive (rare)
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20
Q

Mutations in COL1A1 or COL1A2 produce — pro-alpha collagen chains,
which become — into collagen trimers (esp. affects glycine residues
of gly-X-Y triplet in triple helical domain)

A

abnormal

incorporated

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21
Q

Abnormal collagen molecules incorporated together with normal collagen into
trimers, therefore

A

few or no normal collagen trimers produced

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22
Q

type 3 OI

A

progressive forming type/bones fracture easily

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23
Q

symptoms of type 3 OI (3)

A

short stature, spinal curvature
severe bone deformity
blue sclera

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24
Q

type 3 OI is

A

autosomal dominant

sometimes autosomal recessive

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25
Q

type 3 OI arises from mutations in

A

COL1A1 and COL1A2

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26
Q

type 4 OI

A

severity intermediate between types 1 and 2

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27
Q

type 4 is

A

autosomal dominant

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28
Q

type 4 OI arises from mutations in

A

COL1A2 and rarely COL1A1

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29
Q

Why are many diseases with mutations in
extracellular matrix proteins inherited in a
dominant fashion?

A

polymeric molecules incorporate into the fiber, proteins work together in polymers that they can’t fit together

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30
Q

Group of patients identified as type V OI - clinically similar to type IV but specific

A

clinical features.

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31
Q

Type V - autosomal dominant inheritance pattern but patients had no mutations in

A

collagen genes

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32
Q 
Recessive form(s) of OI long suspected due to
cases where unaffected parents had more than one child with severe
A

bone dysplasia

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33
Q

New — OI types VI and VII proposed

diagnosis based on histology

A

recessive

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34
Q

Types — OI identified more recently

autosomal recessive

A

VIII-XVI

35
Q

None of these forms of OI had mutations in type — collagen genes

A

1

36
Q

Now up to – genes known to cause different forms of OI

A

15

37
Q

CRTAP (cartilage associated protein) forms a complex with (2)

A

cyclophilin
B (encoded by PPIB gene) and prolyl 3-hydroxylase 1 (encoded by
LEPRE1 gene

38
Q

It is the prolyl-3 hydroxylase 1 that actually

— collagen alpha1(I) chain at one specific residue (Pro986)

A

hydroxylates

39
Q

Mutations in CRTAP cause defective 3-prolyl-hydroxylation which delays

A

collagen folding

40
Q

Type 7 OI is caused by a

A

hypomorphic CRTAP defect (severely reduced amounts of normal CRTAP protein).

41
Q

CRTAP null mutations result in a

A

severe lethal form OI (similar to type II)

42
Q

Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone
disorder resembling

A

lethal/severe osteogenesis imperfecta

43
Q

For patients with inherited diseases, you should first look for mutations
in genes already known to cause

A

similar phenotypes

44
Q

For patients with inherited diseases, you should first look for mutations
in genes already known to cause

A

similar phenotypes

45
Q

Then it is often worthwhile to look for mutations in genes of proteins that interact with the known gene or that may be working in the same

A

biochemical pathway

46
Q

What if you have two diseases with phenotypes that are very similar, but which have been associated with completely different genes?
It may be worthwhile to do experiments to determine whether these genes interact in a

A

common biochemical pathway

47
Q

OI can be caused by mutations in (2)

A

type I collagen genes or in genes encoding proteins involved in collagen post-translational
modifications/ regulation of collagen biosynthesis

48
Q

dentinogenesis imperfecta is a hereditory disease of dentin with (5)

A
  • Opalescent/brown teeth that wear easily
  • bulbous crowns
  • narrow roots
  • Small/obliterated pulp chambers
  • frequent splitting of enamel from dentin under occlusal stress
49
Q

type 1 occurs in families with

A

osteogenesis imperfecta (especially type 3, 4) due to mutations in COL1A1 or COL1A2

50
Q

shields type 2

A

not associated with OI (due to mutations in DSPP)

51
Q

shields type 3

A

brandywine type

occurs in racial segregate in maryland, USA (due to mutations in DSPP)

52
Q

brandywine

A

opalescent/brown teeth in patient with osteogenesis imperfecta

53
Q

Teeth in OI patients are more susceptible to

A

wear/breakage and/or enamel fracturing from teeth

54
Q

If untreated – teeth can wear down to

A

gingiva

55
Q

Pulp chamber/root canals may be filled with dentin, so tooth may

A

lose feeling

56
Q

Early identification of OI condition/preventative interventions is important to

A

minimize dental complications

57
Q

Meticulous oral hygiene / regular periodic examinations to identify

A

teeth needing care

58
Q

For tooth extractions, extra support of jaw may be needed to avoid

A

fracturing

59
Q

OI patients increasingly being treated with

A

bisphosphonates

60
Q

consequences of long term bisphosphonate use starting in childhood
not known, but some association with

A

Osteonecrosis of the Jaw in

cancer patients on high dose BPs

61
Q

scurvy is associated with abnormal collagen biosynthesis due to

A

nutritional deficiency in vitamin C (ascorbic acid)

62
Q

dietary vitamin c (ascorbic acid) deficiency leads to

A

scurvy

63
Q

symptoms of scurvy (5)

A

• Lethargy
•Bleeding gums/mucous membranes
•Fragile blood vessels/petechial hemorrage of skin
•Loss of gingival and periodontal collagen fibers/anchoring
fibers - loosening of teeth
•Bone pain

64
Q

— = important co-factor for prolyl and lysyl hydroxylases that
hydroxylate proline/lysine residues

A

Vitamin C

65
Q

If hydroxylation is prevented, unfolded procollagen is (2)

A

retained in ER

and/or degraded

66
Q

Leads to deficient collagen assembly – inability to renew

A

connective

tissue matrix

67
Q

oral manifestations of scurvy (2)

A

gum recession

wobbly teeth bc they’re not attached to the alveolar bone

68
Q

mutations in type 2 collagen is linked to

A

chondrodyplasias

69
Q

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
  • diminished extracellular matrix
  • thick, irregular collagen fibrils
70
Q

over – mutations causing ACGII-HCG reported

A

10

71
Q

Over ten mutations causing ACGII-HCG reported. All involve replacement of — by a bulkier amino acid in triple helical region of α1(II) chain

A

glycine

72
Q

Ehlers danlos syndrome is a heterogeneous group of diseases characterized by (4)

A 
• Fragility of soft connective tissues
• Manifestations in skin, ligaments, 
joints, blood vessels, internal organs
• Clinical spectrum varies from mild skin 
\+ joint hyperlaxity to severe physical 
disability/life threatening complications 
(ruptured arteries)
• Mild skeletal abnormalities (e.g. 
osteopenia)
73
Q

how many subtypes of ED?

A

7

74
Q

ED subtypes are mostly linked to mutations in genes encoding for (2)

A

fibrillar collagens (types 3, 5) or enzymes involved in post translational modifications of collagens

75
Q

glomerulonephritis, endstage kidney
disease, hearing loss (due to disruption of
function of basement membrane)

A

Alport Syndrome

76
Q

Congenital form of muscular dystrophy

A

Bethlem

Myopathy

77
Q 
Inherited connective tissue disorder 
chracterized by blistering of the skin and 
mucosal membranes due to defect in 
anchoring between dermis and epidermis.
(1:50,000).  Defects in enamel/caries
A

Epidermolysis

bullosa (EB)

78
Q

Developmental disorder with eye

abnormalities including retinal detachment

A

Knobloch

Syndrome

79
Q

good pasture syndrome is an — disease

A

autoimmune, rare

80
Q

in good pasture syndrome, autoantibodies produced against non collagenous domains of

A

type 4 collagen alpha 3 chain

81
Q

type 4 (alpha 3) is important in

A

golmerular basement membrane

82
Q

good pasture syndrome leads to problems with (7)

A 
kidney filtration
blood in urine
burning sensation when urinating
nephritis
coughing up blood
fatigue
nausea
83
Q

good pasture syndrome can lead to

A

acute renal failure

Applied Biochemistry (52 decks)

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