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Concepts Of Disease > Musculoskeletal diseases > Flashcards

Musculoskeletal diseases Flashcards

1
Q

What is a dominant negative mutation

A

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

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2
Q

Describe the structure of collagen

A

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

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3
Q

What are the intracellular phases of collagen biosynthesis

A

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

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4
Q

What are the extracellular phases of collagen biosynthesis

A

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

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5
Q

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

A
  1. all autosomal dominant
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6
Q

Describe the features of type II OI

A

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

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7
Q

Which types of OI are excluded and what does this mean

A

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

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8
Q

What types of OI are included and what does this mean

A

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

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9
Q

Describe the features of type I OI

A

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

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10
Q

Describe the features of type III OI

A

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

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11
Q

Describe the features of type IV OI

A

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

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12
Q

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

A

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

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13
Q

What does a mutation 1 COL1A2 allele result in and why

A

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

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14
Q

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

A

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

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15
Q

List some factors that impact the severity of OI

A
  • which gene is mutated
  • nature of the mutation
  • position of the mutation
  • over-modification
  • abnormal molecules giving abnormal fibrils
  • abnormal fibrils
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16
Q

How can the nature of mutation impact the severity of OI

A

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.

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17
Q

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

A

least severe = Ala
most severe = Asp

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18
Q

How does the position of the mutation affect severity of OI

A

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

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19
Q

How does over-modification affect the severity of OI

A

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

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20
Q

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

A

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

21
Q

List some potential treatments of OI

A
  • 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
22
Q

What are examples of locus heterogeneity?

A

Autosomal recessive deafness
• Retinitis pigmentosa - retinal disease with rod and cone degeneration
• Usher syndrome- (autosomal recessive forms) - Profound hearing loss, vestibular dysfunction, retinitis pigmentosa - caused by mutations at any one of 11 loci
• Barnet-bipedal syndrome - night blindness,tunnel vision, learning disabilities, kidney disease, extra toes/ fingers, obesity, gonad abnormalities
• Caused in mutation in any of at least 15 genes that regulate cilia function

23
Q

What is skeletal dysplasia?

A

Clinically and genetically heterogenous disorders of bone
Characterised by abnormalities in patterning, linear growth, differentiation and maintenance of the human Skeleton

24
Q

What is a loss of function disease

A

where the gene product has reduced or no normal function and the mutation to inactivate the gene product will result in the same clinical symptoms

25
Q

What is Chondrodysplasia? What are symptoms?

A

Genetic abnormalities affecting cartilage, leading to short stature
Changes in the size and shape of the limbs trunk and or skull
Disproportionate short stature

26
Q

What causes DMD in men

A

deletion at Xp21 (position 21 on the x chromosome)

27
Q

What are the steps of endochondral ossification? (How long bone develops)

A
  1. Cartilage formation- mesenchymal cells divide and differentiate into chondroblasts- secrete cartilage- become embedded in lacunae within matrix
  2. Vascular invasion and longitudinal growth - Ring of woven bone formed in mid shaft. Osteoclasts allow vascular invasion of woven bone and cartilage- secondary centre of ossification growth plate forms
28
Q

What causes DMD in women

A

autosomal translocation at X:21 (between the X chromosome and autosome 21)

29
Q

What do growth plates do?

A

Regulate the length of bone

30
Q

What type of disorder is DMD

A

X-linked recessive

31
Q

What are the layers of growth plates cartilage?

A

Resting zone
Proliferative zone
Prehypertrophic zone
Hypertrophic zone
Bone zone

32
Q

What is expressed in the resting zone, proliferative, prehypertrophic?

A

Collagen II/ IX/ XI Aggrecan

33
Q

What is an X-autosome translocation in DMD and how can it be screened

A

the tip of the normal chromosome 21 is translocated to the X chromosome. can be screened as chromosome 21 will contain chromosome 21 sequences and X chromosome sequences. the DMD gene sequence is disrupted and product cannot be expressed

34
Q

What is expressed in the hypertrophic zone?

A

Collagens II/ IX/XI, aggrecan, collagen X, collagen X, VEGF MMP13

35
Q

What is achondroplasia?

A

Most common
Mutation in FGFR3 - affects stages between prehypertrophic and hypertrophic

36
Q

What is the genotype of a female with DMD

A

X (normal X)
X:21 (X with blue tip from 21st chrom)
21:X (21st chromosome with the DMD gene)
21 (normal 21st chromosome)

37
Q

What is stickler syndrome?

A

Eyes, ear and skeleton
Associated with early onset of OA (20-30 years)
Ligament laxity
Irregular ossification of epiphysis

38
Q

What happens during X inactivation for a female to have DMD

A

the X chromosome is inactivated, so the X:21, 21:X and 21 chromosomes are still active. can occur as there are two viable copies of the autosome

39
Q

What types of mutations result in DMD

A

60-65% deletions
5-15% duplications
20-35% small mutations, intron deletions, exon insertions

40
Q

What is multiple epiphyseal dysplasia (MED)?

A

Heterogeneous Chondrodysplasia, caused by mutations in a number of genes.
Short bones, irregular metaphyses (neck) is irregular
Abnormal knees
• Phenotypes ranges from mild to severe.
• All forms show early onset of OA.
Mutations in COL9A1, COL9A2,COL9A3- mild disease
3 other loci found that also give MED
• COMP (ecm component)
• Matrilin 3
Diastrophic dysplasia sulphate transporter (DYDST
= Locus heterogeneity

41
Q

What mutations are most likely to result in DMD and why

A

frameshift mutations because they alter the reading frame of the DMD gene

42
Q

What are the causes of chondroplasia?

A

Extracellular matrix protein defects- abnormalities in:
• Types II, IX, X and XI collagen
• Matrilin 3
• COMP
• Prelacan

43
Q

What type of mutation caused Becker’s muscular dystrophy

A

frame neutral deletions. result in a lower expression of dystrophin but still present, so symptoms are less severe

44
Q

What is the most common form of human dwarfism caused by?

A

Gain of function mutation in the GFGR3 gene which affects endochondral ossification

45
Q

Where do gene mutations for DMD occur

A

in gene hot spots at certain exons

46
Q

What is the role of dystrophin and how is it altered in DMD

A

expressed in sarcolemma of skeletal muscle. maintains strength, flexibility and stability of muscle. links the dystrophin-associated complex at the sarcolemma and the cytoskeleton.
in DMD = loss of the complex, cell depletion and necrosis, muscle wasting

47
Q

Why is it hard to treat DMD with gene therapy

A

dystrophin mRNA is too large so takes a long time to be transcribed. muscle cells are post mitotic so unlikely to take up gene therapy

48
Q

What are potential treatments for DMD

A

use mini genes coding for dystrophin crucial domains
substitute dystrophin for trophic
correct the reading frame using exon skipping

49
Q

How can micro and mini dystrophin be delivered

A

AVV vectors - adeno associated viruses

Concepts Of Disease (8 decks)

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