Collagen Structure and Function Part 2

Question 1

osteogenesis imperfecta is a — disease

Answer 1

hereditary

Question 2

osteogenesis imperfecta

Answer 2

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

Question 3

how many people does OI affect in the US?

Answer 3

20,000-50,000

Question 4

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

Answer 4

COL1A1 and COL1A2

Question 5

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

Answer 5

types I, II, III, IV

Question 6

OI is mostly – –

Answer 6

autosomal dominant

Question 7

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

Answer 7

quantitative

qualitative

Question 8

most common/mild type of OI

Answer 8

type 1

Question 9

in type 1, bones are predisposed to

Answer 9

fracture (most occur before puberty)

Question 10

symptoms of type 1 OI

Answer 10

normal stature/blue sclera

Question 11

type 1 OI is

Answer 11

autosomal dominant

Question 12

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

Answer 12

no protein being produced from one allele

Question 13

other allele unaffected therefore patients make

Answer 13

REDUCED amounts of

NORMAL collagen I

Question 14

mutations can be;

Answer 14

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

Question 15

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

Answer 15

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

Question 16

normal protein being made but in reduced amounts is known as

Answer 16

quantitative deficiency

Question 17

most severe form of OI

Answer 17

type 2 (perinatal lethal)

Question 18

symptoms of type 2 OI (2)

Answer 18

numerous fractures and severe bone deformity

short stature

Question 19

type 2 OI is

Answer 19

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

Question 20

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)

Answer 20

abnormal

incorporated

Question 21

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

Answer 21

few or no normal collagen trimers produced

Question 22

type 3 OI

Answer 22

progressive forming type/bones fracture easily

Question 23

symptoms of type 3 OI (3)

Answer 23

short stature, spinal curvature
severe bone deformity
blue sclera

Question 24

type 3 OI is

Answer 24

autosomal dominant

sometimes autosomal recessive

Question 25

type 3 OI arises from mutations in

Answer 25

COL1A1 and COL1A2

Question 26

type 4 OI

Answer 26

severity intermediate between types 1 and 2

Question 27

type 4 is

Answer 27

autosomal dominant

Question 28

type 4 OI arises from mutations in

Answer 28

COL1A2 and rarely COL1A1

Question 29

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

Answer 29

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

Question 30

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

Answer 30

clinical features.

Question 31

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

Answer 31

collagen genes

Question 32

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

Answer 32

bone dysplasia

Question 33

New --- OI types VI and VII proposed | diagnosis based on histology

Answer 33

recessive

Question 34

Types --- OI identified more recently | autosomal recessive

Answer 34

VIII-XVI

Question 35

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

Answer 35

1

Question 36

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

Answer 36

15

Question 37

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

Answer 37

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

Question 38

It is the prolyl-3 hydroxylase 1 that actually | --- collagen alpha1(I) chain at one specific residue (Pro986)

Answer 38

hydroxylates

Question 39

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

Answer 39

collagen folding

Question 40

Type 7 OI is caused by a

Answer 40

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

Question 41

CRTAP null mutations result in a

Answer 41

severe lethal form OI (similar to type II)

Question 42

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

Answer 42

lethal/severe osteogenesis imperfecta

Question 43

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

Answer 43

similar phenotypes

Question 44

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

Answer 44

similar phenotypes

Question 45

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

Answer 45

biochemical pathway

Question 46

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

Answer 46

common biochemical pathway

Question 47

OI can be caused by mutations in (2)

Answer 47

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

Question 48

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

Answer 48

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

Question 49

type 1 occurs in families with

Answer 49

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

Question 50

shields type 2

Answer 50

not associated with OI (due to mutations in DSPP)

Question 51

shields type 3

Answer 51

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

Question 52

brandywine

Answer 52

opalescent/brown teeth in patient with osteogenesis imperfecta

Question 53

Teeth in OI patients are more susceptible to

Answer 53

wear/breakage and/or enamel fracturing from teeth

Question 54

If untreated – teeth can wear down to

Answer 54

gingiva

Question 55

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

Answer 55

lose feeling

Question 56

Early identification of OI condition/preventative interventions is important to

Answer 56

minimize dental complications

Question 57

Meticulous oral hygiene / regular periodic examinations to identify

Answer 57

teeth needing care

Question 58

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

Answer 58

fracturing

Question 59

OI patients increasingly being treated with

Answer 59

bisphosphonates

Question 60

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

Answer 60

Osteonecrosis of the Jaw in | cancer patients on high dose BPs

Question 61

scurvy is associated with abnormal collagen biosynthesis due to

Answer 61

nutritional deficiency in vitamin C (ascorbic acid)

Question 62

dietary vitamin c (ascorbic acid) deficiency leads to

Answer 62

scurvy

Question 63

symptoms of scurvy (5)

Answer 63

• 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

Question 64

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

Answer 64

Vitamin C

Question 65

If hydroxylation is prevented, unfolded procollagen is (2)

Answer 65

retained in ER | and/or degraded

Question 66

Leads to deficient collagen assembly – inability to renew

Answer 66

connective | tissue matrix

Question 67

oral manifestations of scurvy (2)

Answer 67

gum recession | wobbly teeth bc they're not attached to the alveolar bone

Question 68

mutations in type 2 collagen is linked to

Answer 68

chondrodyplasias

Question 69

Achondrogenesis type II / hypochondrogenesis (ACGII-HCG)

Answer 69

- 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

Question 70

over -- mutations causing ACGII-HCG reported

Answer 70

10

Question 71

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

Answer 71

glycine

Question 72

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

Answer 72

``` • 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) ```

Question 73

how many subtypes of ED?

Answer 73

7

Question 74

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

Answer 74

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

Question 75

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

Answer 75

Alport Syndrome

Question 76

Congenital form of muscular dystrophy

Answer 76

Bethlem | Myopathy

Question 77

``` 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 ```

Answer 77

Epidermolysis | bullosa (EB)

Question 78

Developmental disorder with eye | abnormalities including retinal detachment

Answer 78

Knobloch | Syndrome

Question 79

good pasture syndrome is an --- disease

Answer 79

autoimmune, rare

Question 80

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

Answer 80

type 4 collagen alpha 3 chain

Question 81

type 4 (alpha 3) is important in

Answer 81

golmerular basement membrane

Question 82

good pasture syndrome leads to problems with (7)

Answer 82

``` kidney filtration blood in urine burning sensation when urinating nephritis coughing up blood fatigue nausea ```

Question 83

good pasture syndrome can lead to

Answer 83

acute renal failure