A major quest in health care today is elucidating the mechanism for Autism Spectrum Disorders (ASD), one of the leading causes of autistic behavior occurring in 1:150 births. Rett Syndrome (RTT) is a developmental disorder of the brain that occurs in females and is responsible for mental retardation and autistic behavior. RTT falls under the umbrella of ASD. Mutations in the X-linked MeCP2 protein situated on the X chromosome are the cause of this genetic disorder. Phenotypic variation ranging from mild to severe manifestations is observed in RTT. A major determinant of this clinical variability is the pattern of X-chromosome inactivation (XCI), a crucial epigenetic process that occurs early in development to balance the gene dose between XX females and XY males. Female cells undergo a chromosomal-wide silencing of one X chromosome at random to equalize the dose. Favorable XCI that silences the X chromosome with the mutant MeCP2 gene will lessen the severity of symptoms in girls with RTT. Insight into how XCI is regulated will provide understanding in the pathogenesis of RTT the may offer hope in the amelioration of severe phenotypes. These studies have profound impact on allelic expression diseases such as genomic imprinted gene disorders, such as Angelman

Public Health Relevance

Rett Syndrome (RTT) is a neurodevelopmental disorder that is one of the leading causes of mental retardation and autistic behavior in girls affecting 1:1000 females. RTT is a consequence of mutations in the MeCP2 gene that resides on the X chromosome. The phenotypic variation ranging from mild to severe manifestations is seen in RTT and is attributed to the pattern of X-chromosome inactivation (XCI), an epigenetic process that silences one of the two female X chromosomes early in development to balance the gene dosage with XY males. Our laboratory studies two crucial processes in development, the stability of pluripotent stem cells and XCI. Recently we have unraveled a transcriptional circuitry linking XCI and ES cell differentiation. We show that a pluripotent factor binds to the chromatin insulator, Ctcf and is involved in X chromosome fate. Our hypothesis is that the trans-factors that regulate XCI also regulate the local and long-range activity of MeCP2 to alter the RTT phenotype. The long-term goal of this proposal is to elucidate a molecular mechanism for allelic choice in pathologies such as RTT (an autism spectrum disorder) diseases such as Angelman

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH090267-05
Application #
8622218
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2010-08-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$390,481
Indirect Cost
$167,731
Name
Winifred Masterson Burke Med Research Institute
Department
Type
DUNS #
780676131
City
White Plains
State
NY
Country
United States
Zip Code
10605
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