Fragiele X Syndroom

Fragile X Syndrome is one of the leading monogenic causes of intellectual disability and autism, and named after the aberrant (‘fragile’) form of the X-chromosome in these individuals.

Fragile X Syndrome is caused by lack of the fragile X mental retardation protein (FMRP), resulting from an (200 +) expansion of the trinucleotide (CGG) repeat at the beginning (5’ untranslated region) of the fragile X mental retardation 1 gene (FMR1). This causes the loss of FMRP protein.

The Fragile X gene was identified at Erasmus MC (Verkerk, Cell, 1991). The Fragile X gene encodes a protein that is called FMRP1 (Fragile X Mental Retardation Protein). This protein binds mRNA which is crucial in the regulation of protein synthesis following stimulation of group 1 metabotropic glutamate receptors (mGluRs) in dendritic spines. Activation of these receptors, especially the mGluR5 receptor, leads to local translation of specific mRNAs into proteins. It is believed that FMRP plays an important role in the translation of these mRNAs, and that loss of FMRP results in excess protein synthesis.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder causing tremor, ataxia, brain pathology, cognitive loss, dementia and early death in some individuals. Like in Fragile X Syndrome, these individuals carry a mutation in the FMR1 gene. But in this case, it is a Fragile X pre-mutation (an expanded CGG repeat between 50-200). In contrast to Fragile X Syndrome, FXTAS is hypothesized to be caused by a gain-of-function mechanism, i.e. the pre-mutation gives rise to a toxic protein. A hallmark of FXTAS neuropathology in postmortem brain tissue is the presence of ubiquitin-positive intranuclear aggregates in both neurons and astrocytes.

The first mouse model of Fragile X Syndrome was generated at the department of Clinical Genetics, Erasmus MC. Using behavioural and molecular/morphological paradigms in both Fmr1 mice and cultured primary neurons or iPSCs, our research aims to identify possible targets for therapeutic intervention. Social behavior of Fmr1 knockout mice is the primary outcome measure in the preclinical mouse studies. In addition, new strategies are explored using combination therapy. Development and evaluation of successful therapeutic intervention strategies (drugs, combination therapy) from our preclinical work can lead to new clinical trials at ENCORE in patients with Fragile X Syndrome.

For FXTAS research, there is a need to define critical ages when pathology begins, development windows when the disease may be halted or reversed, and the cellular and molecular mechanisms that may serve as therapeutic targets for patients with FXTAS. To address these important needs, we have developed powerful state-of-the-art in vitro and in vivo models of FXTAS, including: primary neurons, mouse and zebrafish models.

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