Reactivating the FMR1 Gene

With $171,600 in funding from FRAXA Research Foundation from 1998-2004, Dr. Andre Hoogeveen and his team at Erasmus University explored methods to reactivate the Fragile X gene.

$171,600 Grant
Andre Hoogeveen, PhD
Principal Investigator

Violeta Stoyanova, MD, PhD
FRAXA Postdoctoral Fellow

Erasmus University
1998-2004 FRAXA Research Grant
$171,600 over 6 Years

by Michael Tranfaglia MD FRAXA Medical Director, 8/1/2004

Several years ago, this group made an interesting finding when they were studying cells from an individual who had an unusual case of Fragile X. This person had a large expansion of the FMR1 gene but it was unmethylated (not shut down), so that the gene continued to function, resulting in normal intelligence. When cells from this unusual individual were fused with typical, fully methylated Fragile X cells in a test tube, the methylated full mutation chromosomes quickly became demethylated and started to function normally. Apparently, there is some active ingredient in the unusual cells which is able to restore function to typical Fragile X cells. The team is working to identify this active ingredient and exploit this knowledge for future treatment.

by Violeta Stoyanova, FRAXA Postdoctoral Fellow, 6/2003

In Fragile X syndrome, the FMR1 gene does not function because it is switched off by a chemical modification, called methylation, of a commanding part of the DNA (the promoter). Our studies were performed by growing cells from Fragile X patients in test tubes. In these cells, we can specifically reverse the methylation of the FMR1 gene – an important step toward restoring its normal function.

Rare individuals exist who have long repeats in their FMR1 gene, but for some unknown reason the gene is not methylated and functions normally, so these people do not have Fragile X. We plan to investigate the pattern of gene expression in these healthy people and compare it to that of Fragile X patients. We hope to identify genes important for switching on (demethylating) the silenced FMR1 gene. We are studying cells from members of a family in which some individuals have a methylated FMR1 gene, and are affected by the syndrome, and others whose FMR1 gene is not silenced, in spite of long repeats. Using this strategy, we hope to identify important players in the process which prevents methylation or is even able to reverse the methylated state of the FMR1 gene in Fragile X patients.

Andre Hoogeveen , PhD

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