genetic diseases Flashcards
what are the symptoms of cystic fibrosis?
sticky mucus lung inflammation (chronic bacterial infections) digestive disorders (pancreatic insufficiency) male infertility caused by the absence of the vas deferens shortened life expectancy
what is the mode of inheritance of cystic fibrosis?
autosomal recessive
what gene does cystic fibrosis effect?
the gene encoding for cystic fibrosis transmembrane regulator
what is the most common CFTR mutation?
F508del
what kind of mutation is F508del?
in frame deletion
deletion of phenylalanine at position 508 in exon 10
what are examples of point mutations in cystic fibrosis?
nonsense mutation G542X
missense mutation G551D `
which mutation affects CFTR mRNA stability?
G542X nonsense mutation in exon 11
GGA to TGA
leads to mRNA degradation
no CFTR production causes a severe phenotype
what mutation affects CFTR protein stability?
F508del
deletion of phenylalanine at the 508 position in exon 10
mRNA is translated but the protein is incorrectly folded
this causes the protein to be degraded
no CFTR produced causes severe phenotype
how do some mutations affect the abundance of CFTR?
some mutations affect splicing
so only a proportion of transcribed RNA is correctly spliced
low levels of mature CFTR translated
less severe phenotype
are the mutations involved in cystic fibrosis gain or loss of function mutations?
loss of function
what are the possible treatments for cystic fibrosis?
physiotherapy to loosen mucus inhaled mucolytics to make mucus less sticky antibiotics to fight infections pancreatic enzyme supplements CFTR potentiators such as ivacaftor CFTR correctors
how does ivafactor work as a treatment for cystic fibrosis?
opens phosphorylated channels, even mutant ones, without the need for the binding of ATP
effective for treating cystic fibrosis caused by mutations like G551D that impair ATP-mediated channel regulation
what is duchenne muscular dystrophy?
a genetic disease causing progressive muscle degeneration and weakness
first affects the muscles of the hips, pelvis, thighs and shoulders
causes wheelchair dependence in adolescence
what is the symptom onset of duchenne muscular dystrophy?
early childhood
what is the mode of inheritance of duchenne muscular dystrophy?
sex linked recessive
what causes duchenne muscular dystrophy?
mutations in the DMD gene which encodes for dystrophin
what is the normal function of dystrophin?
runs along muscle cell membranes helping to keep the muscle cells working correctly
it is part of a protein complex that strengthens and protects muscle fibres
anchors the cytoskeleton to other proteins in the ECM
transfers the force of contraction inside muscle cells outward to the cell membrane
where is the hot spot for large deletions in duchenne muscular dystrophy?
between exons 44 and 55
where is the hotspot for large duplications in duchenne muscular dystrophy?
between exons 2 and 10
what are the most common point mutations in duchenne muscular dystrophy?
nonsense
what are cellular consequences of loss of dystrophin function?
muscle cells become damaged as muscles repeatedly contract and relax with use
damaged fibres weaken and die over time leading to progressive muscle degeneration and weakness
what are treatments for duchenne muscular dystrophy?
ataluren
a small molecule compound used for patients with nonsense mutations
how does ataluren work?
when a premature termination codon is reached by the ribosome, ataluren recruits near cognate tRNA’s
these supress the nonsense mutation and allows the readthrough of the premature termination codon
allows the synthesis of full length protein
what are clinical findings of ataluren in treating duchenne muscular dystrophy?
none of the children in the group taking ataluren lost ability to walk over the 48 weeks of the trial compared to 8% on the placebo
research predicts it could delay loss of walking for up to 7 years
but further work is needed
what is huntingtons disease?
a neurological disorder causing ataxia, chorea, dementia and psychosis
what is the mode of inheritance of huntingtons disease?
autosomal dominant
what is the symptom onset of huntingtons disease?
late onset, middle age
shows anticipation
what is the cause of huntingtons disease?
triplet repeat expansion at 4p16.3
CAG repeat
causes polyQ tail leading to neurodegeneration
is the mutation involved in huntingtons disease a loss or gain of function mutation?
gain of function
what causes trinucleotide repeat expansions?
replication fork slippage
how are neuronal inclusions formed in huntingtons disease?
altered huntingtin protein gets cleaved by caspases
these cleaved fragments form aggregations called neuronal inclusions in the nucleus
there is a reduced expression of brain derived neurotrophic factor which is essential for neuronal survival
leads to neuronal death
what part of the brain is most affected by huntingtons disease?
basal ganglia
what is a possible treatment for huntingons disease?
IONIS-HTTRx
kills mRNA that carries the instructions for the damaged protein
