Ben A. Oostra
Ben Oostra received his Ph.D. in biochemistry from the University of Groningen in 1981, where he studied the regulation of rRNA synthesis in E. coli in the laboratory of M. Gruber. For his postdoctoral training he joined the group of A.E. Smith at the NIMR in Mill Hill, UK to work on tumour forming activities of Polyoma virus. After returning to Holland he joined the group of A.J. van der Eb at the University of Leiden to study adenoviruses. In 1985 he started in the department of Clinical Genetics to identify and characterize genes that are responsible for a number of genetic disorders. His work now concentrates on the study of genes involved in neurogenetic disorders.
Group Members Address Genetic basis of neurogenetic disorders Fragile X syndrome and FMR1 Dementia Complex Disorders Facilities and Expertise Future projects Goals Selected publications Reviews
Group members Rob Willemsen, staff member Andre Hoogeveen, staff member Vincenzo Bonifati, staff member Femke de Vrij, postdoctoral fellow Edwin Mientjes, postdoctoral fellow Violettea Stoyanova postdoctoral fellow Aida Bertoli Avella, postdoctoral fellow Judith Brouwer, Ph.D. student Sandra van 't Padje, Ph.D. student Josien Lavenga, Ph.D. student Alessio di Fonzo, Ph.D. student Maria Luisa Conte, Ph.D. student Cathy Bakker, technician Guido Breedveld, technician Ingeborg van Nieuwenhuizen, technician Herma Zondervan, technician Christan Rohe, technician
Address Erasmus MC Rotterdam Department of Clinical Genetics Dr. Molewaterplein 50 Postbus 1738 3000 DR Rotterdam Tel: +31-10-4087198 Fax: +31-10-4089489 E-mail: b.oostra@erasmusmc.nl Homepage: http://www2.eur.nl/fgg/kgen/
Genetic basis of neurogenetic disorders In the past decade considerable progress has been made in unravelling the etiology of important single gene disorders. In the field of neurological and neuropsychiatric diseases only little progress has been made. It is becoming clear that these disorders are complex and may often result from an interplay of genetic and environmental risk factors. Our group is interested to study the genetic basis for a number of 'brain' disorders, and the (dys)function of the gene(s) involved. We have examined the molecular basis of two monogenetic disorders, fragile X syndrome, causing mental retardation, and FTD, or frontal temporal dementia.
Fragile X syndrome and FMR1 The identification of the FMR1 gene started the era of expanding triplet repeat diseases. In fragile X syndrome patients the repeat has more than 200 CGGs (full mutation) and due to this expansion of the repeat, present in the 5' untranslated region of the FMR1 gene, the promoter region is methylated resulting in silencing of the gene (Fig. 1). The expansion of the CGG repeat to a large repeat only occurs in oocytes and never in sperm, irrespectively of the repeat size in somatic cells. As a result of selection during forming and maturation of primordial germ cells only sperm producing cells with a premutation are present after puberty. The mechanism of the repeat instability occurring during gametogenesis and early embryogenesis is still unclear, mainly due to the lack of a human material. Therefore, we have developed an animal model with an expanded repeat. These mice will enable the study of timing and mechanism of amplification in the mouse germ line. At the same time these mice will be used to study the inclusion bodies seen in the nuclei of neurons in carriers of a premutation.
The identification of normal males with a long unmethylated repeat has learned that it is not the long repeat itself that is causing the disease but the methylation of the promoter of the FMR1 gene during embryogenesis. It has been shown that DNA methylation mediates the forming of a multiprotein repression complex by the interaction of MeCP2 with DNA at methylated cytosine residues and a number of factors including histone deacetylases. This complex formation results in modification of chromatin structure, which might explain the delay in replication of the mutated FMR1 gene. Treatment of cells with demethylating agents results in reactivation of the FMR1 gene. The repression could be alleviated by treatment with deacetylase inhibitors. Further studies will focus on the identification of the factors and enzymes that are involved in the (in)activation of the mutated FMR1 gene. This may eventually lead to strategies to prevent inactivation of the FMR1 gene.
The absence of the FMR1 protein is causing mental retardation, but what is the function of the FMR1 gene. Recent work has indicated that the FMR1 protein might regulate localized protein synthesis. The subcellular behavior of FMRP, including its selective mRNA binding, nucleocyplasmic shuttling, and predominant association with cytoplasmic polyribosomes, has led to the hypothesis that FMRP may play a role in nuclear export of its target mRNAs and further present these mRNAs to the translation machinery (Fig. 1 and 2). The discovery of FMRP-polyribosome association in the neuronal dendritic spine implies the possible involvement of FMRP in modulating localization and/or translation of its target mRNAs in the appropriate compartments. Regulation of localized protein synthesis has been demonstrated to be functionally important in cell growth and polarity development. There is still a lack of knowledge about the specific class of mRNAs whose transport/translation Is affected by the lack of FMRP. We are now examining in more detail the shuttling of FMRP and the identification of the specific mRNAs that can be bound to FMRP. Further studies will be directed towards the detection of differences in (cytoplasmic levels of) these mRNAs in patients and in a developed Fmr1 knockout animal model, using differential DNA chip expression screening. Identification of these mRNAs should help to define the influence of FMRP in mRNA metabolism, and finally to the elucidation of pathogenesis in mental retardation due to the lack of FMRP.
Dementia Still very little is known about genetic factors involved in most cases of dementia. To unravel the genetics of such complex disorders requires a strategy capable of detecting effects of genetic factors, which may depend strongly on the presence of other genetic and/or environmental factors. In collaboration with van Duijn en Hofman (Dept of Epidemiology, EUR) we plan to identify new genes implicated in (late-onset) Alzheimer's diseases and Parkinson's disease. The rational of the newly developed method that will be applied is that in a genetic isolated population the number of genes implicated in a heterogeneous disorder is strongly reduced because of genetic drift. Chances that patients have inherited a disease gene from a common ancestor are therefore high and patients from recently isolated populations with a common ancestor likely share considerable parts of DNA around a disease gene. If multiple genes play a role they can be localized simultaneously. New genes for Alzheimer's diseases and Parkinson's disease will be identified and molecular and biochemical role of these disease genes will be studied.
Complex Disorders In 1995 we have started together with Van Duijn (Dept of Epidemiology, Erasmus MC) our research program “Genetic Research in Isolated Populations” (GRIP). This program is conducted in a genetically isolated population in the Southwest of the Netherlands. As part of the GRIP program, we have studied several complex genetic disorders including diabetes mellitus type 1 and 2, Parkinson’s disease, Alzheimer’s disease, ADHD, and Multiple Sclerosis Using municipal records and genealogical data bases of this isolated population of 20,000 residents, we were able to link most of the patients of each disorder to a common ancestor. We have successfully identified various genes that play an important role in the etiology of major diseases. These genes were sometimes identified through searches through the complete genome. These include a new gene involved in Parkinson’s disease (DJ-1: Bonifati et al Science. 2003), a gene involved in hemochromatosis (SLC11A3: Njajou et al, Nature Genetics 2001) and a gene involved in type 2 diabetes and obesity (LIPIN2: Aulchenko, submitted).
Facilities and expertise EM and fluorescent microscopes Large population based collection of DNA and RNA samples ES cell culture facility Mouse and zebrafish facility
(责任编辑:泉水) |