Brittle Bones Flashcards
Osteogenesis imperfecta
Genetic bone disorder characterized by repeat fracturing and malformation of long bones
Mutation in COL1A1 causes single amino acid substitution in pro collagen precursor of a1(I) collagen
Can cause loss of function or reduced function
Structure of collagen
2 x α-1(I) collagen, 1 x α-2(I) collagen in triple helix structure
Glycine is found in the middle of the chain due to its compact size
Repeated Gly-X-Y sequence, where the glycine side chains occupies the middle of the triple helix due to its compact size
Causes glycine being substituted by cysteine
Cause sulfhydryl chain
What does substitution cause
Steric hindrance
- Preventing the proper formation of the collagen triple helix → introduces kinks and decreases tensile strength
- Formation of inapporpriate disulphide bonds (due to the sulfhydryl chain) between adjacent α1(I) chains
Genetic testing
- Foetal DNA obtain in chorionic villus sampling or amniocentesis
- These are both invasive procedures and there is a risk of miscarriage
- This is used in PCR to amplify sample
- We can then identify it as the mutation region is known
Why do the changes cause altered electrophoresis
- Sequence changes from glycine to cysteine
- Cysteine forms disulphide bonds with other molecules
- 2-ME breaks these to get back to normal strands
- SDS-PAGE sodium dodecyl sulfate poly acrylamide gel electophoresis
Why are some alpha 1(I) chains affected
Only 1 of the 2 copies of ColA1 gene are mutated only some collagen
Total amount of collagen produced is the same but what they’re made by different
What happens in presence of 2-mercaptpethanol
Disulphide binds cleaved allowing chains to migrate according to molecular weight
What happens if you’re heterozygous for a mutation that causes abnormal collagen chains?
Some of your alpha chains are abnormal while other allele is making normal ones
How’s it inherited
Autosomal dominant
Disease severity depends in if you have mutation in OL1A1 gene or COL1A2 gene or both
