Institute Activities and Advances
In 1999, NICHD-supported scientists1 discovered that most girls with Rett syndrome had a change in the pattern of a single gene—the Methylcytosine-binding Protein 2 (MECP2) gene on the X chromosome. Research shows that between 90% and 95% of girls with Rett syndrome have a mutation in this gene.2,3 This gene makes Methylcytosine-binding Protein 2 (MeCP2), which is necessary for the development of the nervous system, especially the brain. The mutation causes the gene to make less than the needed amounts of the protein, or to make a damaged protein that the body can't use. As a result, there may not be enough usable protein for the brain to develop normally.
Researchers are still trying to understand exactly how the brain uses MeCP2 and how problems with the protein cause the typical features of Rett syndrome. Normally, MeCP2 helps to "turn off" certain genes that make different proteins in nerve cells and other cells. Without MeCP2, the body keeps making these products, even when it no longer needs them. After a while, having high amounts of these products in the body may actually start to damage the nervous system and cause the problems of Rett syndrome.
Boys with Klinefelter syndrome
can exhibit the classic Rett phenotype. However, some familial cases of Rett syndrome have been found in which male siblings were born with severe encephalopathy and died by one to two years of age. Genetic analyses showed the same MECP2
mutations as in their sisters with Rett syndrome, leading to the suggestion that Rett syndrome is actually a milder manifestation of these mutations and that boys with no wild-type MECP2
exhibit a more severe phenotype.4
In 2002, scientists funded by the NICHD developed a new mouse model for Rett syndrome. This mouse model more closely mimicked the symptoms of Rett syndrome found in humans than did earlier mouse models. For more on the development of this mouse model, visit the NICHD news release at: http://www.nichd.nih.gov/news/releases/pages/rett_syndrome.aspx
Until 2008, researchers did not know the extent to which MECP2 controlled multiple functions in the brain. That is when NICHD-supported researchers discovered the gene's numerous roles not only as a repressor but also as an activator of thousands of other genes in order to maintain proper brain functions. For more on this research, see NIH Researchers Find That Rett Syndrome Gene is Full of Surprises.
Much of the NICHD's research on Rett syndrome is supported through itsIntellectual and Developmental Disabilities Branch (IDDB). The NICHD has provided grants for research in the following areas:
- Role of MeCP2 in Rett syndrome. A 10-year study is examining the regulation and activity of the MeCP2 protein in cells. Researchers want to determine how these cells are affected by the protein's mutation. The study's long-term goals are to (a) understand why the nervous system functions improperly in patients with Rett syndrome, and (b) determine ways that the nervous system can be regulated to improve patients' intellectual and physical function.5
- Glia cells and Rett syndrome. Glia cells insulate nerves so that they can perform well. Because glia cells use MeCP2 protein to make the insulation (myelin), mutated MeCP2 protein results in poor insulation. One study showed that the addition of new glia cells that make normal MeCP2 protein can stop the symptoms of Rett syndrome in mice.6 Another study found that locomotion and anxiety levels are improved in mutant mice when their glia cells resume manufacture of the MeCP2 protein.6
- Expression of MeCP2 protein. Researchers have determined that some patients with autism spectrum disorders may have a genetic defect that reduces their brain's expression of MeCP2 protein.7
- Co-regulation of the MECP2 gene. The MECP2 gene and the early growth response gene 2 (EGR2) influence each other while the brain develops. Scientists have confirmed that the interaction of these genes is important in people with Rett syndrome and autism.8
Other Activities and Advances
- Through its IDDB, the NICHD provides funding support for the Angelman, Rett, and Prader-Willi Syndromes Consortium, an integrated group of academic medical centers, patient support organizations, and clinical research resources dedicated to conducting clinical research on these disorders to improve the care of patients with Angelman syndrome, Prader-Willi syndrome, and Rett syndrome.9 This Consortium is part of the NIH Rare Diseases Clinical Research Network, teams of doctors, nurses, research coordinators, and research labs throughout the United States working together to improve the lives of people with rare diseases through research.
- The NICHD also supports the International Rett Syndrome Foundation’s effort, known as the North American Database10, a registry of sorts for people with Rett syndrome This comprehensive project, the first of its kind in North America, includes information on 1,928 participants from the United States and Canada who either have Rett syndrome (85.5% typical, 13.4% atypical) or another diagnosis in conjunction with an MECP2 mutation (1.1%). The Database organizes the information by diagnosis, mutation status, and mutation type and frequency. This database provides a unique resource for expanding our understanding of Rett syndrome, for comparison with other national databases, and for future study, including organization of clinical trials based on the expected emergence of fundamental therapies.
- Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2. Nature Genetics, 23(2), 185–188. [top]
- Schollen, E., Smeets, E., Deflem, E., Fryns, J. P., & Mathis, G. (2003). Gross rearrangements in the MECP2 gene in three patients with Rett syndrome: Implications for routine diagnosis of Rett syndrome. Human Mutations, 22, 116–120. [top]
- Zoghbi, H. Y. (2005). MeCP2 dysfunction in humans and mice. Journal of Child Neurology, 20, 736–740. [top]
- Neul, J. L., & Zoghbi, H. Y. (2004). Rett syndrome: A prototypical neurodevelopmental disorder. Neuroscientist, 10, 118–128. [top]
- Schanen, N. C. (2012). Investigation of MECP2 function in Rett syndrome, NIH grant project. Retrieved May 10, 2012, from http://projectreporter.nih.gov/project_info_details.cfm?aid=7884501&icde=12575844&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC [top]
- Derecki, N. C., Cronk, J. C., Lu, Z., Xu, E., Abbott, S. B.,Guyenet, P. G., et al. (2012). Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature, 484, 105–109. [top]
- Lioy, D. T., Garg, S. K., Monaghan, C. E., Raber, J., Foust,K. D., Kaspar, B. K., et al. (2011). A role for glia in the progression of Rett's syndrome. Nature, 475, 497–500. [top]
- Nagarajan, R. P., Hogart, A. R., Gwye, Y., Martin, M. R., & LaSalle, J. M. (2006). Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics, 1(4), e1–11. [top]
- Rare Diseases Clinical Research Network. (2012). Angelman, Rett, and Prader-Willi Syndromes Consortium. Retrieved June 23, 2012, from: http://rarediseasesnetwork.epi.usf.edu/arpwsc/about/index.htm [top]
- Percy, A. K., Lane, J. B., Childers, J., Skinner, S., Annese, F., Barrish, J., et al. (2007). Rett syndrome: North American database. Journal of Child Neurology, Dec;22(12), 1338–41. [top]