RIKEN Brain Science Institute (RIKEN BSI) RIKEN BSI News No. 10 (Dec. 2000)



Genes and Brain Diseases

Dr. Kazuhiro Yamakawa
Head, Laboratory for Neurogenetics

IMAGE
magnified scene by clicking image
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.
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.

IMAGE
magnified scene by clicking image
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).
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.
--
RIKEN BSI NEWS

RIKEN BSI HOME
RIKEN Brain Science Institute (RIKEN BSI)
Copyright All Rights Reserved.