Press Releases

Monica Coenraads
Director of Research, RSRF
Monica Coenraads
203.243.5733 Tools and Targets: RSRF Funds Two New Rett Syndrome Research Projects

July 6, 2006

The Rett Syndrome Research Foundation (RSRF) has recently awarded two new research grants. Michael Greenberg of Harvard Medical School will use the $210,000 G.E.A.R (Grants of Excellence to Accelerate Research) award to develop a set of tools that will be used by the entire Rett Syndrome research community, while Terumi Kohwi-Shigematsu of Lawrence Berkeley National Laboratories will apply her $120,000 award to studying a protein that could be responsible for part of the Rett Syndrome phenotype. This award is part of a three-year grant underwritten by the National Institutes of Health (NIH) and IRSA.

There is always a great deal of excitement surrounding the discovery of the genetic basis of a disorder. Knowing the particular mutation that results in disease gives researchers a key to understanding the cascade of biochemical interactions that cause symptoms - and that might be amenable to treatment. Sometimes, however, the gene discovery raises more questions than it answers. Such is the case with Rett Syndrome (RTT), a developmental disorder that afflicts girls 6-18 months after birth, robbing them of acquired language, manual and social skills and condemning them to a life of constant care. RTT is caused by mutations in MeCP2 (methyl CpG-binding protein 2), which normally acts to control the expression of other genes. Scientists believe that if MeCP2 is not functioning properly, the normal patterns of activation and silencing of certain genes are interrupted.

All this naturally leads to the question: which genes are regulated by MeCP2? The diversity of RTT symptoms— which range from autistic features, stereotyped hand movements, and seizures to irregular breathing patterns, osteoporosis, and gastrointestinal difficulties—raises the possibility that many genes are ultimately involved in producing the syndrome. Yet only a few targets of MeCP2 activity have been discovered so far. One of these, DLX5, was identified by Terumi Kohwi-Shigematsu’s group at Lawrence Berkeley National Laboratory several years ago, in research partially funded by RSRF. DLX5 is involved in bone formation and also regulates the production of an important inhibitory neurotransmitter (GABA or γ-aminobutyric acid). What is particularly interesting about this target gene, however, is that it is the first imprinted gene to be found to depend on MeCP2 activity. Imprinted genes (those whose expression depends on whether they were inherited from the mother or father) are generally involved in either development or behavior. Dysregulation of DLX5 could thus be responsible for at least some of the features of Rett syndrome. Dr. Kohwi-Shigematsu’s lab plans to generate mice that over-express DLX5 to see if this is the case. They are also studying how the expression levels of several other imprinted genes are affected by MeCP2 dysfunction.

How do we find other gene targets of MeCP2 activity? Michael Greenberg's lab at Harvard is tackling this question by developing antibody reagents to MeCP2. Antibodies are proteins produced by the immune system to recognize and bind to one specific antigen, such as a particular virus or bacteria (an antibody can even recognize just a short stretch of amino acids or a protein fragment). Because of this specificity, antibodies can be used to track a protein within the cell. A repertoire of antibodies to various forms of the MeCP2 protein will form a set of "homing devices" that allow RTT researchers to discern precisely where and when MeCP2 is expressed in cells and to trace its interactions with other proteins. Identifying such interactions will help us track down the genes regulated by MeCP2 activity in the nervous system- and by doing so could lead us to molecules that might be amenable to therapies. Dr. Greenberg will make the antibodies developed in his lab available to other scientists in the interest of accelerating research.

Since its inception in 1999, RSRF has awarded over $9 million to leading labs around the world. Especially in an era of budget cuts at the National Institutes of Health, private research funding is necessary to fuel the discoveries that will ultimately yield clinical treatments and a cure for Rett Syndrome. The Foundation will be announcing its 2006 grant awards later this summer.