Musculoskeletal diseases

Question 1

What is a dominant negative mutation

Answer 1

where the mutant gene loses its function and prevents other genes from functioning correctly. common where 1 mutation affects a multimeric protein encoded for by more than 1 gene

Question 2

Describe the structure of collagen

Answer 2

composed of 3 alpha chains, 2 x alpha 1 chains (coded for by COL1A1) and 1 x alpha 2 chain (coded for by COL1A2). Each chain contains the triplet repeat GLY-X-Y repeated 100-400x. Glycine is in the centre

Question 3

What are the intracellular phases of collagen biosynthesis

Answer 3

trancription of the gene to mRNA
translation
proline and lysine hydroxylation
glycosylation of hydroxylysine
triple helix formation
secretion

Question 4

What are the extracellular phases of collagen biosynthesis

Answer 4

propeptide removal from each end
fibrillogenesis - collagen assembles into fibrils
crosslink formation - bonds that stabilise and strengthen collagen fibrils

Question 5

How many types of Osteogenesis imperfecta are there and what type of inheritance are they

Answer 5

4. all autosomal dominant

Question 6

Describe the features of type II OI

Answer 6

lethal
brittle bones
beaded ribs
reduced mineralisation
reduced height
hearing loos
blue sclera
dentinogenesis imperfect = discoloration, thin enamel, teeth ground down to gum level
deformed and fractured bones
caused by point mutation in either COL1A1 or COL1A2

Question 7

Which types of OI are excluded and what does this mean

Answer 7

type I, means the mutation results in a null allele which is not expressed. only half of the collagen is therefore laid down in the matrix, but all collagen deposited is normal

Question 8

What types of OI are included and what does this mean

Answer 8

type II, III, IV. mutation results in reduced secretion of collagen, what is laid down includes abnormal collagen molecules. more severe due to the dominant/negative effect

Question 9

Describe the features of type I OI

Answer 9

mild
normal stature
little bone deformity
blue slcerae
hearing loss
excluded. null allele. 50% less collagen than a healthy person laid down, but all collagen is functional

Question 10

Describe the features of type III OI

Answer 10

severe and progressive
marked bone deformity
minimal mineralisation
short stature
beaded ribs
dentinogenesis imperfecta
caused by point mutations in either COL1A1 or COL1A2

Question 11

Describe the features of type IV OI

Answer 11

mild/moderate bone deformity
variable short stature
normal sclerae
some hearing lost
rare dental problems
mainly caused by mutations in COL1A2 gene

Question 12

What is the dominant/negative effect and how can it impact collagen

Answer 12

when the mutant loses its function but also prevents normal gene products functioning
can disrupt whole multimer structure
can mean that if one collagen alpha chain is disrupted, the entire helix can be.
mutations in either COL1A1 or COL1A2 result in brittle bones. effect can be enhanced due to the mutated chain impacting the function of the normal alpha chains

Question 13

What does a mutation 1 COL1A2 allele result in and why

Answer 13

50% of molecules will be abnormal. because COL1A2 codes for the alpha 2 chain.

Question 14

What does a mutation in the COL1A1 gene result in and why

Answer 14

75% of the molecules will be abnormal. because the COL1A1 gene codes for the alpha 1 chain. therefore more severe than mutations in COL1A2

Question 15

List some factors that impact the severity of OI

Answer 15

• which gene is mutated
• nature of the mutation
• position of the mutation
• over-modification
• abnormal molecules giving abnormal fibrils
• abnormal fibrils

Question 16

How can the nature of mutation impact the severity of OI

Answer 16

change of the Glycine in Gly-X-Y
results in slower rate of triple helix formation and over modification, lowers the thermal stability of the helix and means a slower rate of collagen secretion from the cell. poor molecular packing of fibrils. prevents all processes in collagen synthesis after translation.

Question 17

What are the least and most severe point mutations of Glycine regarding collagen stability

Answer 17

least severe = Ala
most severe = Asp

Question 18

How does the position of the mutation affect severity of OI

Answer 18

if the mutation is nearer the 3 prime C-terminus end, will be more severe and result in a higher degree of post-translational modification. Hydroxylation of lysine to hyroxylysine will occur as well as glycosylation of hydroxylysine. prevents all processes after translation

Question 19

How does over-modification affect the severity of OI

Answer 19

reduces thermal stability of collagen and increases intracellular degradation and slower secretion of collagen

Question 20

How does abnormal molecule shape produced by over-modification affect the severity of OI

Answer 20

abnormal molecules result in abnormal fibrils as there is inefficient cleavage of propeptides which affects fibrillogenesis. abnormal fibrils then give poor templates for mineralisation which is key for bone formation

Question 21

List some potential treatments of OI

Answer 21

• bisphosphonates. given to children and reduces osteoclast activity
• recombinant human growth hormone alleviates short stature in childhood
• teriparatide, effective in mildly affected adults. risk associated with long term treatment and withdrawal can result in osteoporosis
• anti-sclerostin activates Wnt signalling to cause bone formation
• surgery - challenging due to weakness of bones for fixation and needing to repeat operations during growth