Collagen structure and function 2

Question 1

what happens when there is an issue with type I collagen?

Answer 1

osteogenesis imperfecta

Question 2

mutations in what genes account for 90% of OI cases?

Answer 2

COL1A1 and COL1A2

Question 3

how is OI inherited?

Answer 3

mostly autosomal dominant

Question 4

is OI due to quantitative or qualitative abnormalities of collagen I?

Answer 4

both

Question 5

what is the most common type of OI?

Answer 5

type I

Question 6

what is type I OI?

Answer 6

• bones predisposed to fracture (most occur before puberty)
• normal stature/blue sclera
• in most cases, “functional null” allele of COL1A1 or COL1A2 genes leads to no (or greatly reduced amounts) protein being produced from one allele
• Other allele unaffected

Question 7

can patients with type I OI still make normal collagen?

Answer 7

yes- still have one unaffected allele that makes reduced amounts of normal collagen

Question 8

what trimers are formed in type I OI?

Answer 8

normal (encoded by normal allele)- but only half the amount of normal collagen produced
*quantitative deficiency

Question 9

what is the most severe type of OI?

Answer 9

type II

Question 10

what is type II OI?

Answer 10

• Numerous fractures and severe bone deformity
• Short stature
• perinatal lethal
• affects glycine residues that disrupts triple helical structure

Question 11

can patients with type II OI still make normal collagen?

Answer 11

no
- Abnormal collagen molecules incorporated together with normal collagen into trimers, therefore few or no normal collagen trimers produced

Question 12

what is type III OI?

Answer 12

progressive deforming type/ bones
fracture easily
-short stature, spinal curvature
-severe bone deformity
-blue sclera
*can be autosomal recessive

Question 13

what is type IV OI?

Answer 13

severity intermediate
between types I/II
-mutations in COL1A2 and rarely COL1A1

Question 14

why are many diseases with mutations in ECM proteins inherited in a dominant fashion?

Answer 14

bc mutant alleles mixed into normal ones make it hard to form the correct polymer

Question 15

what is type V OI?

Answer 15

“mesh-like” bone histology/ calcification
-autosomal dominant but no mutations in collagen genes

Question 16

what are the autosomal recessive types of OI?

Answer 16

types VI-XVI
*no mutations in type I collagen

Question 17

mutations in CRTAP causes what?

Answer 17

defective 3-prolyl-hydroxylation which delays collagen folding

Question 18

what results from a CRTAP null mutation?

Answer 18

severe lethal form of OI (similar to type II)

Question 19

what are the three components of prolyl-3 hydroxylation complex?

Answer 19

CRTAP
cyclophilin B
prolyl-3-hydroxylase 1 (LEPRE1)

Question 20

what is caused by mutation in the prolyl-3 hydroxylation complex?

Answer 20

does not allow/delay collagen hydroxylation during biosynthesis
-can cause diseases like OI

Question 21

different proteins that act in the same pathway can produce diseases with what?

Answer 21

similar phenotypes

Question 22

what are the two kinds of mutations that can case OI?

Answer 22

-mutations in type 1 collagen genes
-mutations in genes encoding proteins involved in collagen post-translational modifications/regulation of collagen biosynthesis

Question 23

common orofacial manifestations of OI:

Answer 23

-brown/grey discoloration of teeth
-abnormalities of pulp chamber

Question 24

orofacial manifestation of severe forms of OI:

Answer 24

-triangular shaped face
-bossing of the forehead
-low set ears
-mid face deficiency/ malocclusions
-may have blue sclera

Question 25

what is a hereditary disease of dentin?

Answer 25

dentinogenesis imperfecta

Question 26

symptoms of dentinogenesis imperfecta

Answer 26

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

Question 27

which type of dentinogenesis imperfecta occurs in families with OI and is due to mutations in COL1A1 or COL1A2?

Answer 27

type I

Question 28

which type of dentinogensis imperfecta occurs due to mutations in DSPP and is not associated with OI?

Answer 28

type II and type III

Question 29

implications for dental care for patients with OI

Answer 29

* Teeth in OI patients more susceptible to wear/breakage and/or enamel fracturing from teeth *teeth can wear down to gingiva * Pulp chamber/root canals may be filled with dentin, so tooth may lose feeling. * For tooth extractions, extra support of jaw may be needed to avoid fracturing

Question 30

Early identification of OI condition/preventative interventions are important for what?

Answer 30

to minimize dental complications

Question 31

what is the common treatment for OI patients?

Answer 31

bisphosphonates

Question 32

what disease is associated with abnormal collagen biosynthesis due to nutritional deficiency in Vitamin C?

Answer 32

scurvy

Question 33

symptoms of scurvy

Answer 33

-lethargy -bleeding gums/mucous membranes -fragile blood vessels/petechial hemorrhage of skin -loss of gingival and periodontal collagen fibers/anchoring fibers-loosening of teeth -bone pain

Question 34

why does vitamin C matter in the biosynthesis of collagen?

Answer 34

required as a cofactor for hydroxylation

Question 35

what happens if hydroxylation of procollagen is prevented or it is unfolded?

Answer 35

retained in ER and/or degraded -leads to collagen deficiency which causes inability to renew CT matrix

Question 36

what happens is something with type II collagen goes wrong?

Answer 36

chondrodysplasias

Question 37

types of chondrodysplasias

Answer 37

achondrogenesis type II/ hypochondrogenesis (ACGII-HCG)

Question 38

what is thought to cause AGCII-HCG?

Answer 38

involves replacement of glycine by a bulkier amino acid in triple helical region of a1(II) chain

Question 39

symptoms of ACGII-HCG

Answer 39

-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 40

characteristics of Ehlers Danlos syndromes:

Answer 40

-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 41

what disease is caused by mutations in genes encoding fibrillar collagens (types III and V)?

Answer 41

Ehlers Danlos syndrome

Question 42

what can be caused by problems with collagen IV?

Answer 42

kidney problems

Question 43

what is caused by problems with collagen VII?

Answer 43

epidermolysis bullosa -can also have enamel defects

Question 44

what disease is caused by production of autoantibodies against non-collagenous domains of type IV collagen alpha 3 chain?

Answer 44

Goodpasture syndrome

Question 45

what is Goodpasture syndrome?

Answer 45

anti-glomerular basement antibody disease rare autoimmune disease

Question 46

what are issues caused by Goodpasture syndrome?

Answer 46

-kidney filtration -blood in urine -burning sensation when urinating -nephritis -coughing up blood -fatigue -nausea *can lead to acute renal failure