Rett-
Research:
Do you know what hope is?
It's reaching past today
It's dreaming of tomorrow
It's trying a new way
It's pushing past impossible
It's pounding on the door
It's questioning the Answer
It's always seeking more.
Do you know what hope is?
It's rumors of a breakthrough
It's whispers of a cure
A rollercoaster ride
Of remedies unsure
Do you know what hope is?
It's candy for the soul
It's perfume for the spirit
To share it makes you
whole
(unknown)
The discovery of the
responsible gene of
Rett-Syndrome allows research
projects which can contribute
to a better understanding of
the disease and possible therapies.
At the moment a concrete german research project cannot be realized, due to the
lack of financial resources.
This project could offer an approach of a therapy-possibility.
Of
course it is a research project with many
question mark which must be worked
out.
Without the right financial resources, this will be impossible.
And in course of the application of these resources
at European level, vluable time is lost.
Please
support this project with a donation.
It can be a contribution to a better
live of a lot of these girls.
What
does this discovery mean?
What makes this
discovery so important?
What made the discovery so difficult?
How are genetics
involved in Rett-Syndrome
Can males have Rett-Syndrome?
What goes wrong in
Rett- Syndrome?
What does this discovery mean?
A
biological marker that may give a molecular diagnosis!
Note: Mutations in MeCP2 will not be equivalent to a diagnosis
of Rett syndrome alone; RETT is clinically defined,
while MeCP2 mutations are found in individuals who do not
meet the clinical criteria for RS; they can be either more mildly
or more severely affected (i.e. without a period of normal early development. )
A prenatal test to detect RS in families with an affected daughter
(though the risk is less than 1%).
A test for sisters of girls with RS to determine if they are
asymptomatic carriers.
A basis for developing strategies to prevent the
disabling effects of Rett syndrome.
Questions
What makes the discovery so important?
Rett syndrome is the first human disease found to be
caused
by defects in a protein involved in regulation of gene
expression through its interaction with methylated DNA.
This discovery has revealed a new class of genetic
disease that might extend far beyond RS and apply to other
neurodevelopmental disorders, but much more research
must be done before such a connection can be established.
Questions
What made the discovery so difficult?
The 23 human chromosome pairs carry some
100,000 genes.
Finding one specific gene on a chromosome - or worse,
the defect lurking in one of its billions of nucleic acids
- without some sort of clue to its location would be like looking
for the proverbial needle in a haystack.
But what if one took a magnet to that haystack?
One might attract old nails, screws, and other metal scraps,
but would eventually be able to pull out that needle.
"Linkages" or genetic "markers" are segments of DNA
that are inherited with the defective gene from
one generation to the next.
If traits caused by different genes are inherited together
in numerous family members, then the genes are likely to be
fairly close to each other on the chromosome.
Using special enzymes that cut DNA at known spots
along its length, geneticists can subdivide the material,
always searching for a smaller piece that still
contains the defective gene.
Rett syndrome does not yield easily to this approach,
because 99.5% of cases are sporadic,
occurring only once in a family.
It is much easier to map the location of a defective gene
if one can compare DNA from many affected and normal
members of one family, since these family members will have
many DNA sequences in common,
and thus provide genetic markers.
In the rare families in which more than one child
is affected by Rett syndrome, RS might occur in sisters,
half-sisters, identical twins or other relatives.
It almost always occurs in both identical twins and in only
one of a set of fraternal twins.
It has been shown to pass from RS mother to RS daughter.
These very few families with more than one affected girl
enabled researchers to eventually solve the puzzle.
How are genetics involved in
Rett-Syndrome?
Can males have Rett-Syndrome?
Each of us has 46 chromosomes in a set of 23 pairs
in every cell of our bodies except eggs and sperm.
These chromosomes are different sizes and
shapes and contain thousands of genes that act as a
"blueprint" for how each of us develops.
Two determine our sex: the X and Y chromosomes.
Females get one X chromosome from each parent (XX);
males receive an X chromosome from their mothers
and a Y chromosome from their fathers (XY).
Since females have two copies of the X chromosome
and need only one working copy for its genetic information,
they "turn off" the extra X in a process called " X inactivation".
Normal females turn off one X chromosome in each of their
cells (usually about half the cells turn off the mother's X,
and half the father's X) in a random pattern that leaves
them with one functional X in most cells.
Because males lack a back-up copy of the X chromosome
that could compensate for a defective one, mutations
on the X chromosome are often devastating in boys.
The first hypothesis to help narrow the search was
based on the fact that RS is seen only in girls.
This made it likely that RTT is caused by an X-linked
dominant mutation that would be lethal in males.
Exclusion mapping studies in the laboratories of Dr. Eric Hoffman
and Dr. Sakkubai Naidu narrowed the probable location
on the X chromosome to a region known as Xq28.
The International Rett Syndrome Association (IRSA)
collects information on family cases of RS for their kindred
database, which is shared with researchers throughout the world.
A few families with more than one girl affected by Rett
helped researchers narrow the candidate region
from several thousand to several hundred genes.
The Zoghbi and Francke groups had analyzed about two
dozen over a period of several years before locating the
culprit, a gene called MeCP2.
In the case of the RTT gene, MeCP2 the mutation affects
brain development in such important ways that boys die either
before or shortly after birth and never have the chance
to develop actual Rett syndrome.
We know that the severity of the syndrome in girls is a
function of the percentage of cells with a normal copy
of MeCP2 that are left to function after random X inactivation.
If X inactivation happens to turn off the X chromosome
carrying the mutated gene in a large proportion of cells,
the symptoms will be mild. If, instead, a larger percentage
of cells has the healthy X chromosome turned off, the
onset could be earlier and the symptoms more severe.
For example an affected girl might lack a period of
normal infantile development.
Questions
What goes wrong in Rett-Syndrom?
What goes wrong in Rett Syndrome?
During development, a multitude of genes are "expressed"
(translated into proteins) in different tissues of the
body at different times and at different levels.
For example, a hypothetical gene that "comes on"
in brain tissue at, say, day 11 in development may be
drastically reduced in its expression level a week later
when its primary job is done.
The RTT gene, MeCP2, encodes a protein (MeCP2)
involved in one of the many biochemical switches
needed to control the complex expression patterns
of other genes by telling them when to turn off.
This "housekeeping" protein is critical for brain development
and essential for life itself.
Scientists believe that lack of a properly functioning
MeCP2 protein could allow other genes to come on
or stay on at inappropriate stages in development,
disturbing the precisely regulated pattern of development.
If they can find out exactly how this
protein works
in a normal brain, and how mutations affect
brain development, scientists may be able to devise
therapies that interrupt the cascade of deleterious
effects on development.
Questions