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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
NST-2 Subcommittee (NST)
Program Officer
Mamounas, Laura
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Nageshappa, S; Carromeu, C; Trujillo, C A et al. (2016) Altered neuronal network and rescue in a human MECP2 duplication model. Mol Psychiatry 21:178-88
Carvalho, Claudia M B; Vasanth, Shivakumar; Shinawi, Marwan et al. (2014) Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes. Am J Hum Genet 95:565-78
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
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
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
Wiszniewski, Wojciech; Hunter, Jill V; Hanchard, Neil A et al. (2013) TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. Am J Hum Genet 93:197-210
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
Yang, Tianshu; Ramocki, Melissa B; Neul, Jeffrey L et al. (2012) Overexpression of methyl-CpG binding protein 2 impairs T(H)1 responses. Sci Transl Med 4:163ra158
Hanchard, Neil A; Carvalho, Claudia M B; Bader, Patricia et al. (2012) A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the MECP2 duplication phenotype. BMC Med Genet 13:71
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

Showing the most recent 10 out of 21 publications