2002 - Exeter College - University of Oxford

gene responsible is on the X
chromosome, the disease state arises
only in males (who have only one
copy of the X chromosome).
Because females have two X
chromosomes, they essentially have
a spare copy of the gene. A
mutation in the ATRX gene on one
X chromosome is compensated for
by the presence of an intact and
functional ATRX gene on the other
X. Such females are called silent
carriers since they themselves exhibit
none of the features of the disease,
but have a 50% likelihood of
transmitting the disease to any male
offspring and a 50% likelihood of
transmitting the carrier status to any
female offspring. The ATRX
syndrome is one of a group of
around 60 different causes of mental
retardation which are inherited on
the X chromosome. The gene
responsible for the ATRX syndrome
was identified in 1995 in the
laboratory of Professor Doug Higgs
at the MRC Molecular
Haematology Unit within the
Weatherall Institute of Molecular
Medicine at the John Radcliffe
Hospital. Since then research in the
laboratory has been directed
towards understanding what role the
ATRX protein (the product of the
ATRX gene) plays during normal
development and why development
goes wrong in males where the gene
is defective.
Initial research efforts were
directed towards determining the
exact tissues and times at which
ATRX function is required during
normal development. Many of
these experiments have been carried
out in an animal (mouse) model,
where it is possible to analyse the prenatal
developmental stages.
Somewhat surprisingly, it was found
that ATRX is critically required from
a very early stage in development and
that a complete absence of the
protein results in lethality well before
birth. This was a more severe result
than was expected since the patients
that we have been studying are
clearly surviving beyond birth (the
oldest patients under study are now
in their fifties). Upon re-evaluation,
it was found that all patients are
actually making some small amounts
of functional ATRX protein
(although often dramatically reduced
relative to normal individuals).
Clearly a critical amount of ATRX
protein is a requisite for survival to
birth. Our experimental system is
now being manipulated to allow us
to study what role ATRX plays at
later stages of development and in
specifically targeted tissues. This will
hopefully allow a more detailed
analysis of the role of ATRX in
tissues such as the developing brain
and the haematopoietic (blood)
system, where clinical evidence in
human patients suggests that ATRX
is likely to play an important role.
Clearly the product of the
ATRX gene is playing a fundamental
role during mammalian
development. So what is it actually
doing? It was found that the ATRX
.. the disease state arises only
in males
protein is a new member of a family
of related proteins (collectively
referred to as the SNF2 family)
which appear to regulate the activity
of multiple downstream genes by
controlling how those genes have
been packaged into chromatin. Thus
in ATRX patients, where the ATRX
protein is not functioning optimally,
it seems that the resulting failure to
package the DNA correctly at
certain sites causes the genes present
at those sites to be ‘turned on’ or
‘turned off’ inappropriately. ATRX
is tightly associated within the nucleus
of the cell with the DNA which has
been most densely compacted (so
called heterochromatin). It may be
that the remodeling activity of
ATRX is particularly required at
these tightly condensed regions.
ATRX can thus be considered as a
kind of master switch – a problem
in this one gene perturbs the activity
of a variety of other genes. The
effects of mutations in this one gene
(the ‘master switch’) can therefore be
observed in a wide range of
different tissues and systems (notably
blood, brain, skeleton, genitalia) in
ATRX patients. Among other
avenues of research, furture efforts
must be directed towards identifying
the different genes whose activity is
dependent on ATRX. At the
moment we know from the
characteristic blood abnormality in
ATRX patients that the alpha globin
genes are downstream targets for
regulation by ATRX, but while other
target genes must exist (genes which
are important in other tissues) they
are not yet known.
Problems of DNA
packaging are only recently emerging
as a potential disease-causing
mechanism. As well as ATRX,
several other human genetic diseases
have recently been characterised
(notably the Rett syndrome and the
ICF syndrome) which appear to arise
due to a breakdown in the normal
packaging of DNA within the cell.
It is interesting that one common
feature of all these ‘diseases of DNA
packaging’ is some form of mental
impairment, suggesting that the
developing brain may be particularly
susceptible to perturbations in gene
expression which occur when DNA
packaging goes wrong. Apart from
the clinical relevance of research into
these diseases, such research should
further our basic understanding of
how the expression of genes is
regulated in complex organisms.
With the completion of the human
genome sequence we know where
the genes are, but the great potential
of this information will only be fully
exploited when we understand how
the activity of those genes is
controlled.
David Garrick,
MRC Molecular Haematology Unit,
Weatherall Institute of Molecular
Medicine,
John Radcliffe Hospital, Oxford
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16 EXON - Autumn 2002