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genetics of human disease > DMD and CF > Flashcards

DMD and CF Flashcards

1
Q

what is the most common severe recessive autosomal disease in caucasians

A

cystic fibrosis

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2
Q

what is the carrier frequency for CF

A

1/22

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3
Q

what was the old diagnostic test for CF

A

if a child has salty sweat

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4
Q

what is CF caused by

A

loss of function of CFTR gene

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5
Q

what is the most common mutation in CF (accounting for around 70% of CFTR mutations)

A

phe508del

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6
Q

what does the phe508del cause

A

CFTR protein to be incorrectly folded and glycosylated. most of protein then undergoes endoplasmic reticulum associated degradation

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7
Q

90% of CF cases will have at least 1 phe508del allele

A

T

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8
Q

over 2000 private mutations are catelogued for CF. what is a private mutation

A

a rare gene mutation usually found only in a single family or a small populations

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9
Q

what is CFTR’s function

A

pumps chloride ions out of cell

inhibits ENaC channel which causes the inward flow of sodium ions

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10
Q

whats the effect of CFTR inhibiting ENaC and pumping Cl ions out of cell

A

chloride and sodium ions lower water potential so water osmoses into periciliary layer keeping it lubricated

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11
Q

what happens if CFTR is ihibited

A

high ion conc in cell. wwater drawn into cell by osmosis. periciliary layer becomes dehydrated and thick

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12
Q

what are the two branches of therapy for CF

A

treating the symptoms

gene therapy

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13
Q

what are some exampes of treating the symptoms of cF to prolong life expectancy

A 
physiotherapy
DNase
Antibiotics
anti inflammatories
mannitol spray
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14
Q

how does DNase reduce mucus viscosity

A

part of reason mucous gets viscous is white blood cells produce nets of DNA to trap bacteria. DNase breaks down these nets

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15
Q

what is involved in gene therapy

A

introducing gene to cells lining the airway

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16
Q

gene therapy has been disappointing after 30 years of attempts T/f

A

T

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17
Q

what are 2 forms of delivery for gene therapy

A

viral vectors

liposomes

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18
Q

what is the problem of using viral vectors as a form of delivery for gene therapy

A

immune response see them as a threat and prevents repeated therapy

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19
Q

how does the phe508del mutation affect the way that the protein folds

A

affects ATP binding site

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20
Q

what does the less common Gly551Asp mutation leading to CF cause

A

a small fraction of protein to fold an get to the surface but it has less gating activity (stops cl- exiting cell)

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21
Q

what drug helps the phe508del CFTR protein to fold

A

lumacaftor

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22
Q

what drug treats the gating problems caused by Gly551Asp

A

Ivacaftor

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23
Q

combination of lumacaftor and ivacaftor was found to be an effective treatment of CF in clinical trials T/F

A

T

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24
Q

who decides whether drug treatment is cost effective for NHS

A

National institute of health and excellence (NICE)

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25
Q

what does QALY stand for

A

quality adjusted life years

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26
Q

what is the incremental cost effectiveness ratio (ICER) and what must it be to be aceptable

A

cost/QALY

£30,000 per QALY gained

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27
Q

why was the combined treatment not deemed suitable

A

too big ICER

28
Q

Ivacaftor was agreed on treatment of children under 5 despite its ICER of £285,000 due to it being a….

A

ultra orphan drug

29
Q

what is the most common muscular dystrophy

A

duchenne muscular dystrophy

30
Q

what kind of disease is DMD

A

X linked

31
Q

what is the age of onset of DMD

A

3-5 years

32
Q

DMD causes people to have a shorter life span and typically die at about 30 years of

A

respiratory failure

33
Q

the DMD gene is very large, how many exons does it have

A

79

34
Q

dystrophin builds a bridge between actin cytoskeleton within muscle cell through the dystoglycan complex which forms a bridge with laminin 2 which interacts with connective tissue in extracellular matrix outside cell. why is the maintenance of this structure important

A

for regeneration of muscles after minor damage

35
Q

mutations in DMD lead to a

A

permaturely truncated, unstable dysrophin protein

36
Q

what is the difference between becker and duchenne muscular dystrophy

A

mutations which maintain the ORF resulting in a partly functional dystrophin cause BMD. mutations that disrupt the reading frame resulting in an abnormal truncated dystrophin cause DMD

37
Q

the majority of mutations in DMD are intragenic deletions. these occur in 2 recombination hotspots. these are

A

exons 1-20 and exons 44-50

38
Q

what are antisense oligonucleotides

A

Antisense oligonucleotides are synthetic single stranded strings of nucleic acids that bind to RNA and thereby alter or reduce expression of the target RNA

39
Q

what is a morholino

A

chemically modified AON that blocks the access of proteins to mRNA

40
Q

when 48 and 51 are spliced together what does it generat

A

out of frame nonsense codon in exon 51 causes translation to terminate

41
Q

how can you interfere with splicing so you dont include exon 51

A

AON binds to mRNA at splice site and prevents it from being spliced

42
Q

what does AON binding to mRNA at splice site and preventing it from being spliced so exon 51 is skipped in Δ49-50 lead to

A

mRNA where reading frame is restored but dystrophin molecule is shorter. know from becker patients that such protein will have sufficient activity to help clinical features of patient.

43
Q

what does AON binding to mRNA at splice site and preventing it from being spliced so exon 51 is skipped in Δ49-50 lead to

A

mRNA where reading frame is restored but dystrophin molecule is shorter. know from becker patients that such protein will have sufficient activity to help clinical features of patient.

44
Q

what percentage of DMD cases are due to deletions of at least one exon

A

60%

45
Q

what is another AON that is used in the treatment of spinal muscular atropy

A

nusinersen

46
Q

what causes SMA

A

low levels of SMN protein (SMN1 is mutated meaning only SMN2 can produce it) (some of SMN2 is degraded due to alternative splicing that skips exon 7)

47
Q

what does nusinersen do

A

increases level of full length SMN protein by preventing exclusion of exon 7 in SMN2 by stopping factors involved in splicing binding

48
Q

even within normal individuals theres a repeat of trinucleotideT/F

A

T

49
Q

what does anticipation mean

A

the severity/age of onset/penetrance increases in succeeding generations

50
Q

what does CGG expansion in 5’ UTR cause

A

DNA gets methylated and is not transcribed - chromosome fragile sites in metaphase spreads

51
Q

what do CAG repeats in ORF encoding polyglutamine protein cause

A

Huntingtons disease

52
Q

huntingtons can be referred to a gain of function disease. what does this mean

A

only one allele needs expansion for disease to be shown

53
Q

dominant CTG expansions in 3’ UTR lead to what?

A

myotonic dystrophy type 1 and 2

54
Q

huntingtons has an incidence of

A

1:6700

55
Q

what does chorea mean

A

dance like movement

56
Q

describe the neuropathology of huntingtons disease

A

in corpus striatum there is neuronal death and generalised atrophy. general brain shrinkage leading to multisystem CNS disorder

57
Q

where is the polyglutamine tract on the huntingtin protein

A

near N terminus

58
Q

there a series of heat repeats what do these do

A

form interactions with other proteins

59
Q

there are a series of caspase cleavage sites in huntingtin gene. what do these do

A

generate toxic fragment which is translocated to nucleus and forms soluble inclusion bodies

60
Q

there is a sharp cut off for the huntingtons disease phenotype T/F

A

T

61
Q

at what age are there no cases of huntingtons below

A

36

62
Q

onset age is …. correlated with repeat size

A

inversely

63
Q

when does repeat expansion occur

A

during male gametogenesis

64
Q

juvenile onset cases for huntingtons are always children of

A

male sufferers

65
Q

which pathways does huntington disease affect

A

nearly every pathway in a cell

genetics of human disease (10 decks)

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