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What kind of research is being done?
AS is being researched by numerous professionals
in order to more accurately described its origin,
physical signs and symptoms and behavioural
characteristics. Genetics studies have identified
four different ways that Angelman Syndrome can
occur. A very small deletion of a part of chromosome
15 occurs in 70% of individuals with AS and
this is the most common mechanism.
Two smaller subgroups have also been identified
- those who have two copies of chromosome 15
coming from their father - called uniparental
disomy (UPD) and those who have a change in
the controlling centre of chromosome 15 - called
imprinting defects.
In 25% of persons with Angelman Syndrome,
none of the changes mentioned above have been
identified, but other changes to the gene are
being characterised.
In 1997, an Angelman Syndrome gene (UBE3A)
was identified and mutations have now been found
in a few Angelman Syndrome children. For many,
the diagnosis remains clinical in this group,
at present. Correlation of genetics with clinical features
is an area of active research, as there are
apparent differences in the manifestations,
depending on the genetic mechanism.
A major focus of current research is on communication.
Children with AS seem to have much greater receptive
language ability than expressive ability (they
can understand, but cannot talk, or communicate
their understanding easily).
Research is also being done on sleep disorders,
epilepsy and sleep/brain patterns.
Further Research Update: (Ellie Smith
- 23/2/98)
I recall saying to you this time last year -
that we had a great start for AS for 1997 with
the "finding" of the AS gene! In the first issue
of Nature Genetics for 1997, there were 2 publications
- 2 of a kind - back to back - detailing the
work performed, the results and the claim that
we now have the AS gene. The discovery of the
AS gene - UBE3A - is still a very great achievement,
but is not the whole story.
UBE3A is situated exactly within the region
previously narrowed down to be the AS Critical
Region, it contains a promoter region (a CpG
island in OP2, a DNA sequence previously identified
in Sydney), there is a function known for the
gene product and there is significant homology
(similarity) to a mouse. The gene has a protein
product which is a ubiquitin - protein ligase.
All of this is consistent with the claim that
UBE3A is the AS gene. In addition, mutations
in UBE3A have been described in patients with
AS and this is really a most critical finding
for those families. These mutations have been
shown in patients who had previously been tested
and found to be nondeleted, nonUPD and nonimprinted.
(NDUI or triple-non patients) Scientists have
even shown that UBE3A is imprinted in brain
tissue during early development but not in cells
from peripheral blood and skin. In these latter
tissues, UBE3A is expressed from both the maternal
and paternal chromosomes 15. Thus lack of imprinting
in the tissue most studied (blood) has not excluded
UBE3A from being the AS gene. It is in this
respect in particular, that I think that recent
work has been most outstanding and the laboratories
involved must be congratulated, because they
went ahead and followed through with a lot of
work to prove the concept that imprinting could
be tissue and time specific.
So progress into understanding the AS gene
has been made - however, now, only 12 months
later, it seems that UBE3A is not the whole
story. While mutations have been found in some
patients, and for these families, this is the
answer to their diagnostic dilemma, nevertheless
this only seems to account for about 20% of
triple-non patients. What about the rest? There
must still be another factor(s) of crucial importance
to account for the remaining AS patients - now
termed "quadruple-non". Science has been able
to narrow down the field, with each new discovery,
but we haven't got there yet. Molecular research
is still continuing, with DNA sequencing going
along close by but downstream to UBE3A. Research
clinically into the features present in patients
also is continuing, as it may be that partial
phenotypes or atypical patients can be accounted
for by the mechanisms which will be found to
operate in the quadruple-non patients. I will
keep you posted on further progress..............
Ellie Smith. - email:
EllieS@nch.edu.au
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