DMD and CF Flashcards
what is the most common severe recessive autosomal disease in caucasians
cystic fibrosis
what is the carrier frequency for CF
1/22
what was the old diagnostic test for CF
if a child has salty sweat
what is CF caused by
loss of function of CFTR gene
what is the most common mutation in CF (accounting for around 70% of CFTR mutations)
phe508del
what does the phe508del cause
CFTR protein to be incorrectly folded and glycosylated. most of protein then undergoes endoplasmic reticulum associated degradation
90% of CF cases will have at least 1 phe508del allele
T
over 2000 private mutations are catelogued for CF. what is a private mutation
a rare gene mutation usually found only in a single family or a small populations
what is CFTR’s function
pumps chloride ions out of cell
inhibits ENaC channel which causes the inward flow of sodium ions
whats the effect of CFTR inhibiting ENaC and pumping Cl ions out of cell
chloride and sodium ions lower water potential so water osmoses into periciliary layer keeping it lubricated
what happens if CFTR is ihibited
high ion conc in cell. wwater drawn into cell by osmosis. periciliary layer becomes dehydrated and thick
what are the two branches of therapy for CF
treating the symptoms
gene therapy
what are some exampes of treating the symptoms of cF to prolong life expectancy
physiotherapy DNase Antibiotics anti inflammatories mannitol spray
how does DNase reduce mucus viscosity
part of reason mucous gets viscous is white blood cells produce nets of DNA to trap bacteria. DNase breaks down these nets
what is involved in gene therapy
introducing gene to cells lining the airway
gene therapy has been disappointing after 30 years of attempts T/f
T
what are 2 forms of delivery for gene therapy
viral vectors
liposomes
what is the problem of using viral vectors as a form of delivery for gene therapy
immune response see them as a threat and prevents repeated therapy
how does the phe508del mutation affect the way that the protein folds
affects ATP binding site
what does the less common Gly551Asp mutation leading to CF cause
a small fraction of protein to fold an get to the surface but it has less gating activity (stops cl- exiting cell)
what drug helps the phe508del CFTR protein to fold
lumacaftor
what drug treats the gating problems caused by Gly551Asp
Ivacaftor
combination of lumacaftor and ivacaftor was found to be an effective treatment of CF in clinical trials T/F
T
who decides whether drug treatment is cost effective for NHS
National institute of health and excellence (NICE)
what does QALY stand for
quality adjusted life years
what is the incremental cost effectiveness ratio (ICER) and what must it be to be aceptable
cost/QALY
£30,000 per QALY gained
why was the combined treatment not deemed suitable
too big ICER
Ivacaftor was agreed on treatment of children under 5 despite its ICER of £285,000 due to it being a….
ultra orphan drug
what is the most common muscular dystrophy
duchenne muscular dystrophy
what kind of disease is DMD
X linked
what is the age of onset of DMD
3-5 years
DMD causes people to have a shorter life span and typically die at about 30 years of
respiratory failure
the DMD gene is very large, how many exons does it have
79
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
for regeneration of muscles after minor damage
mutations in DMD lead to a
permaturely truncated, unstable dysrophin protein
what is the difference between becker and duchenne muscular dystrophy
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
the majority of mutations in DMD are intragenic deletions. these occur in 2 recombination hotspots. these are
exons 1-20 and exons 44-50
what are antisense oligonucleotides
Antisense oligonucleotides are synthetic single stranded strings of nucleic acids that bind to RNA and thereby alter or reduce expression of the target RNA
what is a morholino
chemically modified AON that blocks the access of proteins to mRNA
when 48 and 51 are spliced together what does it generat
out of frame nonsense codon in exon 51 causes translation to terminate
how can you interfere with splicing so you dont include exon 51
AON binds to mRNA at splice site and prevents it from being spliced
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
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.
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
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.
what percentage of DMD cases are due to deletions of at least one exon
60%
what is another AON that is used in the treatment of spinal muscular atropy
nusinersen
what causes SMA
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)
what does nusinersen do
increases level of full length SMN protein by preventing exclusion of exon 7 in SMN2 by stopping factors involved in splicing binding
even within normal individuals theres a repeat of trinucleotideT/F
T
what does anticipation mean
the severity/age of onset/penetrance increases in succeeding generations
what does CGG expansion in 5’ UTR cause
DNA gets methylated and is not transcribed - chromosome fragile sites in metaphase spreads
what do CAG repeats in ORF encoding polyglutamine protein cause
Huntingtons disease
huntingtons can be referred to a gain of function disease. what does this mean
only one allele needs expansion for disease to be shown
dominant CTG expansions in 3’ UTR lead to what?
myotonic dystrophy type 1 and 2
huntingtons has an incidence of
1:6700
what does chorea mean
dance like movement
describe the neuropathology of huntingtons disease
in corpus striatum there is neuronal death and generalised atrophy. general brain shrinkage leading to multisystem CNS disorder
where is the polyglutamine tract on the huntingtin protein
near N terminus
there a series of heat repeats what do these do
form interactions with other proteins
there are a series of caspase cleavage sites in huntingtin gene. what do these do
generate toxic fragment which is translocated to nucleus and forms soluble inclusion bodies
there is a sharp cut off for the huntingtons disease phenotype T/F
T
at what age are there no cases of huntingtons below
36
onset age is …. correlated with repeat size
inversely
when does repeat expansion occur
during male gametogenesis
juvenile onset cases for huntingtons are always children of
male sufferers
which pathways does huntington disease affect
nearly every pathway in a cell
