Rett Syndrome (RTT) is an Autism Spectrum Disorder (ASD) of known monogenic cause. It represents one of the leading causes of intellectual and developmental disabilities in females. RTT is caused by mutations or duplications of the gene encoding MeCP2, a methyl DNA binding protein thought to modulate global gene expression. Mice with loss of function of MeCP2 (knock-out) have a range of physiological and neurological abnormalities that mimic the human syndrome. Despite the fact that most RTT-causing mutations are clustered at the methyl-CpG binding domain of MeCP2, it is not known if disruption of methyl-CpG recognition alone is sufficient to cause RTT. Moreover, the mechanisms by which MeCP2 dysfunction leads to RTT remain poorly understood. Recently, we have developed a knock-in mouse carrying a missense mutation of MeCP2 at Threonine 158 (T158A). T158 is located at the methyl-CpG binding domain of MeCP2 and is the most common missense mutation associated with human patients. Preliminary studies suggest T158A mutation impairs the ability of MeCP2 to recognize methylated DNA. In addition, T158A knock-in mice appear to show similar symptoms to MeCP2 knock-out mice. Thus, within the scope of this New Program Development Award, we plan to focus on the following specific aims: 1) Phenotypic characterication of the MeCP2 T158A knock-in mice in comparison to MeCP2 knock-out mice. 2) Dissection of the molecular and cellular functions of MeCP2 with MeCP2 T158A knock-in mice. In the long run, we hope to not only gain insights into the pathogenic mechanisms of RTT, but also uncover therapies and cures for ASD.

Public Health Relevance

Current treatment options for ASD are limited, and clinical progress has been slow due to a poor understanding of ASD etiology. At present, Rett Syndrome is the only ASD with a known cause. Thus, understanding the pathogenic basis of RTT will not only shed light on other ASD, but also improve methods for the diagnosis and treatment of other intellectual and developmental disabilities.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Center Core Grants (P30)
Project #
5P30HD026979-24
Application #
8523942
Study Section
Special Emphasis Panel (ZHD1-MRG-C)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
24
Fiscal Year
2013
Total Cost
$64,742
Indirect Cost
$42,175
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Carlson, G C; Lin, R E; Chen, Y et al. (2016) Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating. Neuroscience 322:408-15
Chen, Yong; Bang, Sookhee; McMullen, Mary F et al. (2016) Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia. Mol Neurobiol :
Ghosh, Mausam; Lane, Meredith; Krizman, Elizabeth et al. (2016) The transcription factor Pax6 contributes to the induction of GLT-1 expression in astrocytes through an interaction with a distal enhancer element. J Neurochem 136:262-75
Opladen, Thomas; Lindner, Martin; Das, Anibh M et al. (2016) In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. Mol Genet Metab 117:19-26
Port, Russell G; Gaetz, William; Bloy, Luke et al. (2016) Exploring the relationship between cortical GABA concentrations, auditory gamma-band responses and development in ASD: Evidence for an altered maturational trajectory in ASD. Autism Res :
White, Rachel S; Bhattacharya, Anup K; Chen, Yong et al. (2016) Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1. Mol Brain 9:38
Edgar, J Christopher; Fisk 4th, Charles L; Liu, Song et al. (2016) Translating Adult Electrophysiology Findings to Younger Patient Populations: Difficulty Measuring 40-Hz Auditory Steady-State Responses in Typically Developing Children and Children with Autism Spectrum Disorder. Dev Neurosci 38:1-14
Port, Russell G; Edgar, J Christopher; Ku, Matthew et al. (2016) Maturation of auditory neural processes in autism spectrum disorder - A longitudinal MEG study. Neuroimage Clin 11:566-77
Antezana, Ligia; Mosner, Maya G; Troiani, Vanessa et al. (2016) Social-Emotional Inhibition of Return in Children with Autism Spectrum Disorder Versus Typical Development. J Autism Dev Disord 46:1236-46
Mlynarski, Elisabeth E; Xie, Michael; Taylor, Deanne et al. (2016) Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome. Hum Genet 135:273-85

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