DMD and CF

Question 1

what is the most common severe recessive autosomal disease in caucasians

Answer 1

cystic fibrosis

Question 2

what is the carrier frequency for CF

Answer 2

1/22

Question 3

what was the old diagnostic test for CF

Answer 3

if a child has salty sweat

Question 4

what is CF caused by

Answer 4

loss of function of CFTR gene

Question 5

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

Answer 5

phe508del

Question 6

what does the phe508del cause

Answer 6

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

Question 7

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

Answer 7

T

Question 8

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

Answer 8

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

Question 9

what is CFTR’s function

Answer 9

pumps chloride ions out of cell

inhibits ENaC channel which causes the inward flow of sodium ions

Question 10

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

Answer 10

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

Question 11

what happens if CFTR is ihibited

Answer 11

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

Question 12

what are the two branches of therapy for CF

Answer 12

treating the symptoms

gene therapy

Question 13

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

Answer 13

physiotherapy
DNase
Antibiotics
anti inflammatories
mannitol spray

Question 14

how does DNase reduce mucus viscosity

Answer 14

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

Question 15

what is involved in gene therapy

Answer 15

introducing gene to cells lining the airway

Question 16

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

Answer 16

T

Question 17

what are 2 forms of delivery for gene therapy

Answer 17

viral vectors

liposomes

Question 18

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

Answer 18

immune response see them as a threat and prevents repeated therapy

Question 19

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

Answer 19

affects ATP binding site

Question 20

what does the less common Gly551Asp mutation leading to CF cause

Answer 20

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

Question 21

what drug helps the phe508del CFTR protein to fold

Answer 21

lumacaftor

Question 22

what drug treats the gating problems caused by Gly551Asp

Answer 22

Ivacaftor

Question 23

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

Answer 23

T

Question 24

who decides whether drug treatment is cost effective for NHS

Answer 24

National institute of health and excellence (NICE)

Question 25

what does QALY stand for

Answer 25

quality adjusted life years

Question 26

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

Answer 26

cost/QALY | £30,000 per QALY gained

Question 27

why was the combined treatment not deemed suitable

Answer 27

too big ICER

Question 28

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

Answer 28

ultra orphan drug

Question 29

what is the most common muscular dystrophy

Answer 29

duchenne muscular dystrophy

Question 30

what kind of disease is DMD

Answer 30

X linked

Question 31

what is the age of onset of DMD

Answer 31

3-5 years

Question 32

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

Answer 32

respiratory failure

Question 33

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

Answer 33

79

Question 34

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

Answer 34

for regeneration of muscles after minor damage

Question 35

mutations in DMD lead to a

Answer 35

permaturely truncated, unstable dysrophin protein

Question 36

what is the difference between becker and duchenne muscular dystrophy

Answer 36

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

Question 37

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

Answer 37

exons 1-20 and exons 44-50

Question 38

what are antisense oligonucleotides

Answer 38

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

Question 39

what is a morholino

Answer 39

chemically modified AON that blocks the access of proteins to mRNA

Question 40

when 48 and 51 are spliced together what does it generat

Answer 40

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

Question 41

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

Answer 41

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

Question 42

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

Answer 42

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.

Question 43

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

Answer 43

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.

Question 44

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

Answer 44

60%

Question 45

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

Answer 45

nusinersen

Question 46

what causes SMA

Answer 46

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)

Question 47

what does nusinersen do

Answer 47

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

Question 48

even within normal individuals theres a repeat of trinucleotideT/F

Answer 48

T

Question 49

what does anticipation mean

Answer 49

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

Question 50

what does CGG expansion in 5' UTR cause

Answer 50

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

Question 51

what do CAG repeats in ORF encoding polyglutamine protein cause

Answer 51

Huntingtons disease

Question 52

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

Answer 52

only one allele needs expansion for disease to be shown

Question 53

dominant CTG expansions in 3' UTR lead to what?

Answer 53

myotonic dystrophy type 1 and 2

Question 54

huntingtons has an incidence of

Answer 54

1:6700

Question 55

what does chorea mean

Answer 55

dance like movement

Question 56

describe the neuropathology of huntingtons disease

Answer 56

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

Question 57

where is the polyglutamine tract on the huntingtin protein

Answer 57

near N terminus

Question 58

there a series of heat repeats what do these do

Answer 58

form interactions with other proteins

Question 59

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

Answer 59

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

Question 60

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

Answer 60

T

Question 61

at what age are there no cases of huntingtons below

Answer 61

36

Question 62

onset age is .... correlated with repeat size

Answer 62

inversely

Question 63

when does repeat expansion occur

Answer 63

during male gametogenesis

Question 64

juvenile onset cases for huntingtons are always children of

Answer 64

male sufferers

Question 65

which pathways does huntington disease affect

Answer 65

nearly every pathway in a cell