Dit document omvat mijn samenvatting (info slides + notities) van Les 2 van het vak Neurogenetics gegeven door Rosa Rademakers. Ik heb dit voor elke les, buiten les 10. Daarvan heb ik wel notities bij de slides. Je mag me hiervoor ook altijd contacteren :))
Class 2
Genetic mechanisms in neurological disorders
- Mutations a+ecting the protein coding region of the genome can be classified by
their impact on protein function
- Loss of function
o Complete loss of the protein: null, loss-of-function, amorph
o Reduction of protein’s ability to work: hypomorph, reduction-of-function
- Gain of function
o Increase in the protein’s function: hypermorph, gain-of-function
o Acquisition of a new function (or ectopic expression of the function):
neomorph, dominant gain-of-function
o New function or protein doing their function in the wrong part of the body
Loss-of-function mutations
- Loss-of-function usually means that less of a protein is made or that some
function of the protein has been compromised.
- Loss-of-function mutations are usually recessive, since in most cases, a single
"good" copy of the gene will su+ice ... but there are two common types of
exceptions (dominant loss-of-function)
- Haploinsu+iciency: One copy is not enough
- Dominant-negative mutation: The defective allele interferes with the function of
the wild-type copy. This is common with proteins that form multimers.
- Often mutational heterogeneity in loss-of-function mutations because there are
many ways of inactivating a gene including frame-shifting, nonsense, major
splice-site, missense and whole gene deletions.
Gain of function
- Gain-of-function can lead to a more active protein (increase in the function),
though it often refers to the protein taking on a novel (toxic) function. The
mutation may also lead to the accumulation or deposition of toxic RNA or
protein.
- Gain-of-function mutations are usually dominant, since the wild-type copy of the
gene is not able to counterbalance the toxic e+ect of the mutation.
- The resulting phenotypes of gain-of-function mutations are typically associated
with mutational homogeneity. They include unstable oligonucleotide expansions
or specific activating missense mutations, or a mutation that results in
overexpression, but not a great range of di+erent types of mutations.
It is very di+icult to determine disease mechanism, and often still changes after initial
reports on the disease. Combination of loss and gain of functions also common (e.g.
repeat expansions, see Class III)
, Example I. spinal muscular atrophy
- Neuromuscular disease
- Can be variable
- Most of time young individuals
o Sometimes live beyond childhood
- Mutation in SMN1 are the cause of this disease
o Recessive loss of function mutations
Complex disease mechanism involving spilcing
- Exon 7 is a splice enhancer
- You get skipping of exon 7 in 90% of the time -> very unstable proteins that gets
degraded
- Children who have 2 deletions
o Normally lethal, because of 10% protein production by SMN2
Extra copies of SMN2 determine phenotype
- Some one copy on each chromosome
- Some have more copies
- The worst category, the non sitters, most of then have 2 copies -> 10% protein
production by SMN2
- Type 3 and 4 can become older and they have sometimes 3, 4 or even 5 copies ->
much more SMN
Consideration on clinical testing in SMA
- Genetic testing in parents to see what the changes are that the next child got the
same disease
- Sometimes you have duplication of SMN1 -> two copies on the same
chromosome -> higher risk on getting a child with SMA
- Missense change = total levels are normal, but one of the copies is not working
Example II. CADASIL
- E+ect the small blood vessels in the brain
- Autosomal dominant -> every person have 50% to give the disease to the child
- Man and females equally a+ected
- Migraine
o Over 50% persons have migraine with aura
- By the time that the patients are in thy 50% they show cognitive decline -> lead to
dementia
- Significance compromise of the blood supply
- Complicated to diagnose
o It started with migraine with aura
o Mood disturbances
o …
è Di+erent phases and with everyone it starts at an another time
Cadasil is caused by mutations in NOTCH3
- Caused by an heterowygous mutation in NOTCH3
- Depositing of NOTCH3 receptor
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