The X-linked neurodevelopmental disorder Rett syndrome (RTT) is one of the leading causes of mental retardation (MR) and autism in females. 80% of girls with RTT have mutations in the gene encoding methyl-CpG- binding protein 2 (MeCP2), a transcriptional repressor that binds methylated cytosines. The phenotypic consequences of MECP2 mutations range from classic RTT in those with random X chromosome inactivation (XCI) to mild or even no MR in girls with favorable XCI. We hypothesize that impaired MeCP2 function leads to misexpression of genes crucial for neuronal development, which mediates RTT pathogenesis and some forms of autism and MR. Project 1 (Dr. Zoghbi) will create mouse models for RTT for pathogenesis and therapeutic studies, use microarray technology to evaluate alterations in gene expression in the RTT mice, and genotypic sporadic females and female relatives of RTT girls with MR, autism, or learning disabilities. Project 2 (Drs. Glaze and Percy) will clinically characterize the girls studied in Project 1 and test whether methyl donors (folate and betaine) can ameliorate neurologic dysfunction in RTT by enhancing cytosine methylation. Project 3 (Dr. Van den Veyver) will characterize expression of MECP2 variants in developing brain and in RTT tissue; correlate effects of MECP2 mutations on gene expression in human cell lines, mouse embryonic stem cells and Xenopus with expression data from mouse models (Project 1) and study changes in DNA methylation by methyl donors administered to mice in Projects 1 and 2. The Morphology-Neuropathology portion of the Core (Dr. Armstrong) will do systematic morphological analyses on mouse models (Project 1) and conduct immunohistochemical studies on mouse and human tissues (Project 3). Through these multi-disciplinary studies we hope to identify the cause of MR/LD or autism in a subset of patients, to gain insight into the pathogenesis of RTT, and to develop therapeutic strategies for this and related late-onset neurodevelopmental diseases.
| 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 |
| Tofil, Nancy M; Buckmaster, Mark A; Winkler, Margaret K et al. (2006) Deep sedation with propofol in patients with Rett syndrome. J Child Neurol 21:210-3 |
| Kankirawatana, P; Leonard, H; Ellaway, C et al. (2006) Early progressive encephalopathy in boys and MECP2 mutations. Neurology 67:164-6 |
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