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| Fig.1 |
DSCAM,
a candidate gene responsible for mental retardation in Down syndrome. DSCAM was
identified in the critical region on chromosome 21, and was expressed in neural
tissues. DSCAM protein is expressed on cell surface. Cells expressing DSCAM tend
to aggregate into clusters. |
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At
the Beginning
Have you ever seen a girl in a wheelchair, who always makes a gesture of wringing
her hands in front of her incessantly on the street? The girl most probably has
Rett syndrome. This syndrome, occurring one in 10,000 to 15,000 girls, is characterized
by serious mental retardation, hand wringing in particular, and autism. Patients
with this disease seem to grow up normally for one or two years, and then begin
to exhibit obvious mental retardation as soon as they begin to speak. The parents,
having raised their child with affection feel great pain because of the changes
in their beloved child. From July 23 to 27, 2000, an international conference
for Rett syndrome took place in Karuizawa, to which we who are involved in the
study of this disease were invited. All parents of patients who participated in
this conference were young, and we felt great unity within the families and parentsﾕ
deep affection for these patients.
Genetic
Diseases and Us
Because hereditary diseases
are rare, many people may consider that these have nothing to do with them. It
is certain that most hereditary diseases occur relatively rarely and the incidence
of a hereditary disease is approximately one in 10,000 to 20,000 individuals.
However, given the presence of thousands of genetic diseases which have already
been confirmed, it is imaginable that there are a large number of people suffering
from hereditary diseases. Furthermore, patients with Down syndrome or the above-mentioned
Rett syndrome are born from parents with a normal karyotype or with the normal
implicated gene at respective incidence rates (one in 700 for the case of Down
syndrome). These diseases are not inherited, and in this respect these are not
hereditary diseases. However, these are still called genetic diseases because
they are caused by abnormal gene or gene dosage. Since many patients, including
those with Down syndrome and Rett syndrome, have little opportunity to appear
openly in society, it is true that we ourselves can recognize only less the number
of diseases and their severity, than the reality. Meanwhile, in the case of a
recessive hereditary disease with an incidence of one in 10,000 individuals, one
in 50 possesses the disease-causing gene. Considering all hereditary diseases,
it can be said that we all possess several decades or more of genes which can
cause hereditary diseases. Therefore, genetic diseases should be a deep concern
for all of us.
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| Fig.3 |
Mutations
found in the MECP2 gene in Japanese patients with Rett syndrome. Mutations are
concentrated on functional domains, MBD (methyl-binding domain) and TRD (transcriptional
repression domain). |
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Mental
Retardation and Genes
Our study team aims to
identify genes associated with neurological diseases and to analyze their functions.
One of our themes is mental retardation. Currently, projects for Down syndrome
and Rett syndrome are being pursued. As known by many people, Down syndrome, which
includes mental retardation with the highest incidence, is primarily caused by
triplication or translocation of chromosome 21. Patients with Down syndrome also
suffer from congenital heart disease, digestive organ disease and leukemia. In
less than one percent of our cases, only part of chromosome 21 was in a triploid
form. Comparing the triploid form with the patientﾕs symptoms will help us identify
which part of the chromosome is significantly related to the onset of which symptoms.
We identified the so-called DSCAM gene from the region which is believed to be
associated with disease phenotypes including mental retardation, and clarified
that DSCAM functions as a neural cell adhesion molecule (Fig. 1). As recently
reported in newspapers, the entire sequence of chromosome 21 was decoded, revealing
that there are approximately 20 genes in the critical region and a total of 225
genes in the entire chromosome 21. DSCAM is the largest (834 kb) gene among these
genes. By transforming the part of chromosome 16 of a mouse which corresponds
to a part of chromosome 21 in a human, a mouse model of Down syndrome has been
generated. This mouse presents behavior similar to mental retardation and possesses
three copies of DSCAM. At present, by regulating the expression level of DSCAM
in the mouse, we are attempting to confirm whether this gene is indeed related
to the onset of mental retardation. With respect to Rett syndrome, only recently
(in October, 1999), a study group in the United States reported that MECP2 is
the gene responsible for Rett syndrome. Their achievements were enthusiastically
welcomed by academic associations and parties of patientsﾕ parents. We have observed
many variations in this MECP2 gene in Japanese patients with Rett syndrome, and
have found that the type of variation is related to the severity of the syndrome
(Fig. 2). It has been proposed that the MeCP2 protein, when bound to a region
on methylated DNA, suppresses the expression of downstream genes. The actual genes
whose expression are regulated by MeCP2 or the number of these genes remain to
be clarified; however, we estimate that the number of genes should be quite high.
In other words, because the amount of MeCP2 protein in a patientﾕs brain is reduced
by half, many unregulated genes are expressed in amounts greater than the normal
amount. Such an event causes some abnormalities in the brain and leads to the
development of mental retardation. Clarification of the pathogenesis of mental
retardation is still a long process.
Epilepsy
and Genes
Epilepsy is a disease
that afflicts one to two percent of the total population at some point in their
lives. As a cause for epilepsy, injury in the head, stroke and infectious disease
are cited; however, many cases of epilepsy are believed to be caused by abnormalities
in genes. More than 20 genes responsible for epilepsy, including those coding
for ion channels, have been identified to date. Analysis of these genes will lead
to the improvement of existing treatments for epilepsy and to the development
of treatments for intractable epilepsy. In our laboratory, we are also pursuing
the identification of genes causing juvenile myoclonic epilepsy, childhood absence
epilepsy and temporal lobe epilepsy using samples from hundreds of patients in
Japan and overseas by methods such as genetic linkage analysis. One of our projects
is the study of Laforaﾕs disease, which is symptomatic epilepsy. Laforaﾕs disease
is a highly severe disease with patients exhibiting symptoms such as dementia
and ataxia besides ictus epilepticus; patients typically die within 10 year after
the onset of the disease. In 1998, a novel gene, EPM2A, was reported as the gene
causing Laforaﾕs disease. Recently, we found that the protein coded by this gene
named laforin was a dual-specific phosphatase which coexists with polyribosomes,
and abnormalities were observed in the intracellular localization for laforin
proteins with some disease mutations. At present, by generating mouse models and
identifying their ground substances, we are attempting to evaluate the function
of the laforin protein. It is true that the Laforaﾕs disease is relatively rare,
with an incidence of one in approximately 20,000 individuals. However, a group
of malignant epilepsies called progressive myoclonus epilepsy, to which Laforaﾕs
disease belongs, is characterized by common symptoms. Understanding of the function
of laforin may therefore lead not only to the clarification of the pathogenesis
of Lafora's disease but also to understanding of other symptomatic epilepsies.
We believe that our study will lead to the development of treatments for these
devastating diseases in the near future.
At
the End
The major goal of the
BSI to which we belong is to elucidate how the brain functions. To achieve this
goal, teams in each field, such as "understanding", "protection"
and "creation," are actively pursuing their studies. Since a field like
protection of the brain aims at understanding diseases and applying to both diagnosis
and treatment as a primary aim, some may consider that this field is not directly
involved in real understanding of brain itself. However, to understand the brain,
approaches from various aspects are desired. Among these approaches, the study
of neurological diseases is undoubtedly a highly effective approach. Meanwhile,
it is also necessary that we pursue our studies while always keeping in mind the
way our results can be returned to society. We believe that identification and
analysis of the genes related to neurological diseases will lead not only to the
accurate diagnosis and treatment of diseases but also to the better understanding
of brain functions, such as memory, learning and emotions at the molecular level,
and ultimately understanding of the mind. We will further proceed to reinforce
joint studies with researchers from different fields and utilize the merits of
BSI.
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