MECP2 spectrum disorders include classic Rett syndrome, females with Rett syndrome variants, Angelman-like phenotypes, autism, mental retardation, learning disabilities, attention disorders, as well as males with Rett syndrome, fatal infantile encephalopathy, mental retardation with tremors/movement disorders and/or seizures, or early onset psychosis in the form of bipolar disorder or schizophrenia. The mechanism by which alterations in the MeCP2 protein itself, or the dosage of MeCP2 protein, result in the various disease phenotypes is unclear. My proposal seeks to understand these mechanisms so that rational treatments can be developed to help children with MECP2 spectrum disorders. My goal is to determine how loss of function and missense mutations, as well as duplication of MECP2, cause neurological dysfunction.
The specific aims of my proposal are 1) to identify global patterns of chromatin modification and 2) to identify specific MECP2 target genes in human and mouse models of MECP2 spectrum disorders and 3) to test the hypothesis that therapy targeted to epigenetic modifications improves symptoms in mouse models of MECP2 dysfunction. I propose to use ChlP-on-chip technology to test the hypothesis that loss of function and missense mutations, as well as duplication of MECP2, cause neurological dysfunction by altering chromatin states at specific loci resulting in the misregulated expression of select genes, and that restoration of the normal chromatin state will improve symptoms associated with a subset of MECP2 alterations. My long term goal is to become an independent physician scientist with a research program designed to investigate the molecular basis of autistic spectrum disorders, mental retardation, and developmental epilepsy syndromes and ultimately help clinicians provide accurate diagnostic, prognostic, and therapeutic information to patients and their families. Baylor College of Medicine provides the perfect environment for my success. My mentor, Dr. Huda Zoghbi, is an internationally known physician/scientist with a tremendous training record. Departmental support of my research career, interaction with a scientific advisory committee, and formal coursework at Baylor and elsewhere will also help me to achieve my goals.
|Peters, S U; Hundley, R J; Wilson, A K et al. (2013) Brief report: regression timing and associated features in MECP2 duplication syndrome. J Autism Dev Disord 43:2484-90|
|Campbell, Ian M; Rao, Mitchell; Arredondo, Sean D et al. (2013) Fusion of large-scale genomic knowledge and frequency data computationally prioritizes variants in epilepsy. PLoS Genet 9:e1003797|
|Carvalho, Claudia M B; Pehlivan, Davut; Ramocki, Melissa B et al. (2013) Replicative mechanisms for CNV formation are error prone. Nat Genet 45:1319-26|
|Peters, Sarika U; Hundley, Rachel J; Wilson, Amy K et al. (2013) The behavioral phenotype in MECP2 duplication syndrome: a comparison with idiopathic autism. Autism Res 6:42-50|
|Ramocki, Melissa B; Scaglia, Fernando; Stankiewicz, Pawel et al. (2011) Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2. Am J Med Genet A 155A:1574-80|
|Murdock, David R; Clark, Gary D; Bainbridge, Matthew N et al. (2011) Whole-exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria. Am J Med Genet A 155A:2071-7|
|Breman, Amy M; Ramocki, Melissa B; Kang, Sung-Hae L et al. (2011) MECP2 duplications in six patients with complex sex chromosome rearrangements. Eur J Hum Genet 19:409-15|
|Campbell, Ian M; Kolodziejska, Katarzyna E; Quach, Michael M et al. (2011) TGFBR2 deletion in a 20-month-old female with developmental delay and microcephaly. Am J Med Genet A 155A:1442-7|
|Carvalho, Claudia M B; Ramocki, Melissa B; Pehlivan, Davut et al. (2011) Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 43:1074-81|
|Ansari, Safdar A; Hunter, Jill V; Nassif, Lisa M et al. (2011) Bilateral in utero cerebellar infarction. J Child Neurol 26:895-9|
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