COD Osteogenesis imperfecta Flashcards
What is a dominant negative effect?
Mutant gene not only loses its own function but also prevents other gene products from functioning correctly
Common where mutation affects a multimeric protein encoded by more than 1 gene
eg osteogenesis imperfecta
Describe collagen
Composed of 3 alpha chains
Each alpha chain contains the triplet repeat (Gly-X-Y)
Part of the molecule exists as a triple helix with glycine in the centre
Describe Osteogenesis imperfecta
4 main types Caused by mutations in COL1A1 or COL1A2 genes Encode type 1 collagen Affects 1 in 15-20000 people Mild to lethal phenotypes Brittle bone disease is the main one Type II OI is lethal Beaded ribs, reduced mineralisation and deformed bones
How do you diagnose OI?
Clinical and radiographic
There can be fractures from mild trauma, reduced height, flat midface, bowing deformities of long bones
Also, hearing loss and blue sclera
Barrel chest, scoliosis, osteopenia
A bone biopsy can be done but this is very invasive
It is now more common to do genetic testing
What is Dentinogenesis imperfecta?
Abnormality in dentin Tooth discolouration Brown or blue/grey Narrow pulp chambers Thin enamel Teeth rapidly ground down to gum level
Describe type II OI and type III OI and type IV OI
Type 2 is lethal
Type 3 is severe and progressive
Stature short in both, dentinogenesis imperfecta, beaded ribs
Both are included type
Caused by point mutation in COL1A1 or COL1A2 gene
Type IV is mild/moderate
Variable short stature, no dentinogenesis imperfecta (rare), some hearing loss
Also included type
Caused by point mutation in COL1A2 gene
What is the difference between included and excluded OI?
Excluded (Type 1)
- mutation results in a null allele
- There is only half of the collagen laid down in the matrix but what is deposited is all normal
Included (Type II, III, IV)
- mutation results in reduced secretion of collagen
- What is laid down in the matrix includes abnormal collagen molecules
- Due to the dominant/negative effect, included types are generally more severe than excluded types
Fill in the blanks
Type 1 collagen is composed of (?) alpha 1 (COL1A1) chains and (?) alpha 2 (COL1A2) chains
Mutations in 1 COL1A2 allele coding for the alpha 2 chain will result in (?%) of the molecules being abnormal
Mutations in 1 COL1A1 allele coding for the alpha 1 chain will result in (?%) of the molecules being abnormal
2 1 50 75 Mutations in COL1A1 are more severe
Point mutations are the main cause of type II OI
Point mutations that result in a change of glycine in a GLY-X-Y triplet are the major cause of OI
Substitution of glycine in the triple helical domain results in what?
Slower rate of triple helix formation and over-modification
Lower triple helix thermal stability
Slower rate of secretion of collagen molecules from the cell
Poor molecular packing of molecules into fibrils
True or false
The order of severity of OI phenotype for different Glycine substitutions in collagen is:
Lowest - Ala & Ser
True
What are the factors that affect severity of OI?
Which gene (eg COL1A1 or COL1A2)
Nature of mutation (eg which aa replaces glycine)
Position of the mutation (The triple helix of collagen assembles from the C-terminal end. Mutations affecting the 3’ end of the mRNA disrupt triple helix formation. This results in a higher degree of post-translational modification)
Over modification (reduces the thermal stability of collagen - increased intracellular degradation and slower secretion)
Abnormal molecules give abnormal fibrils (over modified molecules - inefficient cleavage of propeptides - affect fibrillogenesis)
Abnormal fibrils (poor templates for mineralisation)
What are some OI treatments?
Bisphosphonates - reduce osteoclast activity but efficacy in terms of reduced fracture number is moderate in children but not proven in adults
Anabolic therapy -
Recombinant human growth hormone
Alleviates short stature when given in childhood
Teriparatide
Only effective in mildly affected adults
There are risks associated with long term treatment and withdrawal - osteoporosis
Anti-sclerostin
Activates wnt signalling to cause bone formation
Why is Orthopaedic Surgery challenging?
Due to the weakness of the bones for fixation
