Samenvatting Les 2 'Genetic mechanisms'

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