OI

Question 1

What is type I collagen responsible for?

Answer 1

Most abundant form in humans - >90%

Contributes to bone, tendon and skin.

Question 2

What is type II collagen responsible for?

Answer 2

Found in cartilage and the vitreous humour of the eye

Question 3

What is type III collagen responsible for?

Answer 3

Found in skin, blood vessels, uterus and intestine

Question 4

What is type VII collagen responsible for?

Answer 4

Forming anchoring fibrils in the skin

Question 5

Describe collagen

Answer 5

Triple helical molecules
Glycine-Xaa-Yaa repeat, X&Y are usually proline in type one
Usually 338 repeats
Left handed individual chains
Left handed triple helices

Question 6

How are triple helices of collagen formed?

Answer 6

Translation by RER
Individual chains expressed with N and C termini propeptides which are later cleaved
Three collagen chains associate from their C-terminal propeptides towards the N-terminal to produce procollagen
The chains are modified during assembly:
-Glycosylation
-Hydroxylation of some prolines and lysines
Propeptides are removed when the chains are outside the cell
Crosslinking

Question 7

What does over-modification cause?

Answer 7

Missense variants result in glycines being replaced by any one of eight other amino acids
Bulkier substituting amino acids cause delay of helix formation and lead to over-modification of the collagen
The closer the variant to the C-terminal, the greater the over-modification

Question 8

What are the effects of over-modified collagen?

Answer 8

Increased intracellular degradation so reduced amounts reaching the extracellular matrix
Increased endoplasmic stress, compromising cell function
Exported molecules produce distorted collagen fibrils that provide a poor scaffold for calcification

Question 9

What disorders are Type I collagen defects associated with?

Answer 9

Osteogenesis imperfecta

Ehlers-Danlos syndrome type VII

Question 10

What disorders are Type II collagen defects associated with?

Answer 10

Various chondrodysplasias

Question 11

What disorders are Type III collagen defects associated with?

Answer 11

Ehlers-Danlos Syndrome type IV

Aortic aneurisms

Question 12

What disorders are Type VII collagen defects associated with?

Answer 12

Dystrophic epidermolysis bullosa

Question 13

Describe Type I OI

Answer 13

Classic non-deforming OI
Blue sclerae
Autosomal dominant inheritance
2 genes

Question 14

Describe Type II OI

Answer 14

Perinatal lethal
Autosomal dominant and recessive forms
5 genes

Question 15

Describe Type III OI

Answer 15

Progressively deforming OI
Normal sclerae
Both autosomal dominant and recessive forms
14 genes

Question 16

Describe Type IV OI

Answer 16

Common variable OI
Normal sclerae
Both autosomal dominant and recessive forms
7 genes

Question 17

Describe Type V OI

Answer 17

OI with calcification in interosseus membranes
Autosomal dominant inheritance
1 gene

Question 18

How many subtypes of OI are there?

Answer 18

Many - hard to classify

Better classification system described by Van Dijk and Sillence 2014

Question 19

Give details of the genetic basis of Type I OI

Answer 19

Linkage to either the COL1A1 or COL1A2 genes
Semi-private (infrequently are variants found in more than a few families)
Occasional De Novo
Mostly nonsense and frameshift variants
Small percentage of cases are due to amino acid substitutions, exon-skipping variants or deletions of entire exons.

Question 20

Describe the collagen production in Type I OI

Answer 20

Mostly results from reduced amounts of normal type I collagen - leads to haploinsufficiency

Question 21

Give details of the genetic basis of non-type I OI

Answer 21

Mostly due to AA substitutions but some exon-skipping variants and exon deletions
Mostly de novo, which initially made OI appear recessive
Variants are also semi-private

Question 22

What is the gradient model of severity in OI?

Answer 22

The connection of all types of OI as a spectrum of diseases of the same protein - collagen Byers et al 1985
Type I < TypeIV < Type III < Type II

Question 23

What is the regional model in OI?

Answer 23

Theory that certain domains of the triple helix can tolerate variants better than others
Such domains are regions that are not vital for interaction of collagen with other extracellular matrix proteins
The model works best for variants of the COL1A2 chain

Question 24

What is the evidence for the regional model in OI?

Answer 24

COL1A2 lethal domains coincide with binding domains for interaction with other extracellular matrix proteins

Question 25

What is CRTAP?

Answer 25

Cartilage associated protein Part of the 3-hydroxylation complex Variants associated with osteogenesis imperfecta

Question 26

What is the 3-hydroxylation complex?

Answer 26

``` Complex which is responsible for the hydroxylation of collagen Made up of; CRTAP P3H1 (prolyl-hydroxylase) Cyclophilin B (PPIB) ```

Question 27

Give some non-collagen mutations which result in an OI phenotype

Answer 27

Recessive SERPINH1 first found in dachshunds, encodes HSP47 chaperone FKBP10 encodes FK506 chaperone SP7 gene encodes transcription factor PLOD2 encodes lysyl hydroxylase-2 BMP1 encodes the peptidase for C-propeptide cleavage (recessive)

Question 28

Give details on SP7

Answer 28

Transcription factor "master regulator" of bone cell differentiation

Question 29

Give details on PLOD2

Answer 29

encodes lysyl hydroxylase-2 | Creates telopeptide cross-linking sites in collagen

Question 30

What genetic variants cause EDS type VII?

Answer 30

Dominant: skipping of exon 6 of COL1A1 and COL1A2, which code for the N-terminal Recessive: ADAMTS2 codes for a protease

Question 31

What is mutational heterogeneity?

Answer 31

When the same mutation causes different disease in different people When different mutations cause the same disease in different people

Question 32

What is the evidence for mutational heterogeneity?

Answer 32

Variants in COL1A1 and COL1A2 and IFITM5 can result in the same severity of disease Variants in COL1A1 and COL1A2 can cause either OI or EDS TVII