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The research program of the Euro-MRX consortium

The research program described below is the backbone of the Euro-MRX consortium. You will find information on the general goals, the expected achievements, background information of the field of study, and experimental approach of this project.

General goals

The research program has the following aims:

  • Providing a large central database of X-linked mental retardation (XLMR) families, which is connected to a repository of patient cell lines.
  • Identification of additional MRX genes.
  • Elucidation of the biological role of MRX genes, which will lead to an understanding of how mutations give rise to mental retardation in humans.

Expected achievements

The consortium has clinical and molecular data from a collection of more than 600 XLMR families. Of most (but not all) families a cell-line is present. Organising this data into a database and connecting the cell-lines to the database will make the knowledge available to the entire scientific community. This will expedite the identification of new genes involved in XLMR. Although a large number of genes has already been shown to be implicated in XLMR, we still expect the identification of more than 20 XLMR genes in the coming years.

Much of our efforts will be dedicated to the development of diagnostic tools, such as next generation sequencing, to identify the genetic defect in these families. Families in which the causative gene has been indentified will be clinically examined in great detail. The results will be compared with those of other families, in order to reveal subtle phenotypic features associated with a specific mutation. The identified features can then be used for guidance in DNA diagnostic testing.

Background information

One of the three criteria of the definition of mental retardation is defined as a person having an IQ lower than 70. A person with an IQ lower than 50 is considered to be severely handicapped. About 2% of the population is mentally retarded, most of which are males. Despite its high incidence, little is known about the biological basis of this disease.

The diagnosis of MR is complex because a combination of multiple genes and environmental factors may be involved. In 1996 the first XLMR gene was identified, called FMR2, which is located adjacent to the fragile X-E (FRAXE) site on Xq28. Up till now, 16 non-syndromic and 66 syndromic XLMR genes have been identified.

With the completion of the Human Genome Project, the sequence of almost the entire X-chromosome and its encoded genes are known. A major challenge will be to establish the involvement of these genes in human X-linked disorders. The current data suggest that most genes only have a minor contribution to the incidence of XLMR in the population. Hence, identification of all causative genes, or a significant portion thereof, requires the availability of large cohorts of XLMR patients to be analysed.

Once most of the genes involved in XLMR have been identified, the major challenge will be to explain how mutations lead to mental impairment. One important question to address is how mutations in so many genes lead to mental retardation. A partial explanation for this may be that mental retardation is the final consequence of any process that leads to subnormal neural functioning.

However, the alternative theory that genes underlying XLMR may be involved in the same or similar biological pathways may also be part of the explanation. This notion is strengthened by the observation that five of the known XLMR genes are involved in the same signalling pathway of Rho GTPases. For this reason we are studying the role of the Rho GTPases and its interacting proteins in neural development and plasticity, and explore the effect of mutations found in XLMR patients.

Experimental approach

The starting point in our investigations is a collection of clinical and molecular data of more than 600 XLMR families, which was established by the Euro-MRX consortium from 1996 till date. This collection has been instrumental in the identification of 17 of the 82 XLMR genes presently known. These genes have proved to be causative of XLMR in only a small percentage of cases (1% on average). Therefore, in order to reach the goal of identifying additional XLMR genes, our collection of families needs to be expanded still.

The techniques that will be employed in identifying novel XLMR genes, include the following:

  • a highly standardised strategy for the characterisation of X-chromosomal breakpoints which are associated with XLMR
  • genomic microarrays for the detection of X-chromosomal microdeletions by Comparative Genomic Hybridisation (arrayCGH)
  • next generation sequencing

Once causative XLMR genes are identified, their biological role will be established by the use of neuronal cell systems and animal model systems, such as the fruit fly and the mouse. These studies will explore the pathways involving Rho-GTPases and their contribution to micro-anatomical abnormalities underlying mental retardation. The results of these studies should allow us to asses the in vivo function of novel XLMR genes in:

  1. regulating the cytoskeleton
  2. development of neural morphology and connectivity.

The in vivo results will be translated to a molecular level by the use of microarray techniques. These techniques allow us to study the gene expression profiles in cultured neuronal cells and in relevant brain tissue (like the cerebral cortex and hippocampus) in XLMR mouse models. Hereby, abnormal gene expression will be revealed in known or even unknown signalling pathways.

Besides molecular and cellular research, clinical studies will be performed on families in which the causative gene has been identified. By comparing these clinical results with those of other XLMR families, subtle phenotypic features will be recognised which are associated with a specific mutation. This will refine the clinical classification of XLMR, of which the benefits are twofold:

  1. improvement of diagnostic testing
  2. acceleration of the identification of novel XLMR