Rett syndrome (RTT, MIM 312750), an X-linked disorder, is a leading cause of mental retardation and autistic features in females. Affected girls achieve the expected physical and intellectual milestones until some point between 6 and 18 months of life, when they lose whatever language skills have acquired, their cranial growth slows, and they develop ataxia, gait apraxia, seizures, breathing dysrhythmias, and autistic behavior. Our laboratory recently found that mutations in the gene encoding methyl- CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT). We also found that the phenotypic consequences of MECP2 mutations vary from normal or mild learning disability to classic RTT, depending on the pattern of X chromosome inactivation (XCI), MeCP2 mediates transcriptional silencing by binding 5 methyl-cytosines with its methyl- binding domain (MBD) while the transcriptional repressor domain (TRD) recruits a co-repressor a complex containing Sin3A and histone deacetylase. We thus propose that the RTT phenotype is caused by altered expression of genes that are key for normal neuronal development, and that mutations in MECP2 are responsible for some cases of autism, mental retardation or learning disability. The overall goal of this project is to test these main hypotheses and to investigate the mechanism or learning disability. The overall goal of this project is to test these main hypotheses and to investigate the mechanism of pathogenesis in RTT. To define the full phenotypic spectrum of MECP2 mutations we will screen a large number (approximately 800-1,000) of females who have a diagnosis of learning disability, mental retardation, autism, and atypical or classic RTT for mutations in this gene. To carry out pathogenesis studies we will first generate and characterize mouse models of RTT using both gene targeting and transgenic approaches. To identify genes whose proper expression depends on normal MeCP2 function, we will use microarray expression analysis to compare gene expression in mutant and wild-type mice at different times during nervous system development. Lastly, we will investigate possible therapies (such as treatment with methyl group donors, agents which can modulate pathways we uncover through pathogenesis studies or supportive therapies) in mice to determine the effects of early intervention on outcome. These studies should provide insight about the pathogenesis of RTT as well as common disabling neurodevelopmental disorders such as autism and non-syndromic mental retardation and could lead to effective therapy in the future.
| De Maio, Antonia; Yalamanchili, Hari Krishna; Adamski, Carolyn J et al. (2018) RBM17 Interacts with U2SURP and CHERP to Regulate Expression and Splicing of RNA-Processing Proteins. Cell Rep 25:726-736.e7 |
| Zoghbi, Huda Y; Beaudet, Arthur L (2016) Epigenetics and Human Disease. Cold Spring Harb Perspect Biol 8:a019497 |
| Suter, Bernhard; Treadwell-Deering, Diane; Zoghbi, Huda Y et al. (2014) Brief report: MECP2 mutations in people without Rett syndrome. J Autism Dev Disord 44:703-11 |
| Glaze, Daniel G; Percy, Alan K; Motil, Kathleen J et al. (2009) A study of the treatment of Rett syndrome with folate and betaine. J Child Neurol 24:551-6 |
| Neul, J L; Fang, P; Barrish, J et al. (2008) Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 70:1313-21 |
| Percy, Alan K (2008) Rett syndrome: recent research progress. J Child Neurol 23:543-9 |
| Percy, Alan K; Lane, Jane B; Childers, Jerry et al. (2007) Rett syndrome: North American database. J Child Neurol 22:1338-41 |
| Alvarez-Saavedra, Matias; Saez, Mauricio A; Kang, Dongcheul et al. (2007) Cell-specific expression of wild-type MeCP2 in mouse models of Rett syndrome yields insight about pathogenesis. Hum Mol Genet 16:2315-25 |
| Moretti, Paolo; Zoghbi, Huda Y (2006) MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 16:276-81 |
| Tofil, Nancy M; Buckmaster, Mark A; Winkler, Margaret K et al. (2006) Deep sedation with propofol in patients with Rett syndrome. J Child Neurol 21:857-60 |
Showing the most recent 10 out of 32 publications
