Autism is an increasingly common disorder of complex etiology, affected by both genetic and environmental influences. Autism has several phenotypic features in common with the neurodevelopmental disorders Rett syndrome and Angelman syndrome. Rett syndrome (RTT) is an X-linked dominant disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2 (MeCP2). Methylation of CpG dinucleotides and methyl-specific binding proteins are part of an epigenetic pathway essential for parental imprinting and chromatin dynamics during normal brain development. Angelman syndrome (AS) is an imprinted disorder caused by maternal deficiency of chromosome 15q11-13. In addition, MECP2 mutations have been found in a few patients diagnosed with AS and autism and 15q11-13 duplications are the most common cytogenetic abnormality found in autism. Together these findings support the broad premise that these three distinct genetic syndromes share overlap in their pathogenic mechanisms. This research proposal will focus on the hypothesis that MECP2 regulates gene expression in the 15q11-13 region, and that aberrations in this regulatory pathway may contribute to phenotypic features of autism-spectrum disorders.
The first aim of the proposal is to determine the effect of MeCP2 deficiency on gene expression in the imprinted 15q11-13 locus by several quantitative approaches.
The second aim of the proposal is to determine the mechanism by which MeCP2 regulates gene expression within 15q11-13.
The third aim i s to investigate expression defects in MeCP2 and target genes in the 15q11-13 region in multiple autism brain samples. These studies aim to uncover important mechanistic similarities between the overlapping neurodevelopmental disorders RTT, AS, and autism. The successful completion of these studies should yield findings to help develop better diagnostic and treatment modalities for autism-spectrum disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD048799-04
Application #
7423917
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Kau, Alice S
Project Start
2005-08-10
Project End
2010-05-30
Budget Start
2008-05-31
Budget End
2009-05-30
Support Year
4
Fiscal Year
2008
Total Cost
$344,947
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Woods, Rima; Vallero, Roxanne O; Golub, Mari S et al. (2012) Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Hum Mol Genet 21:2399-411
Martins-Taylor, Kristen; Schroeder, Diane I; LaSalle, Janine M et al. (2012) Role of DNMT3B in the regulation of early neural and neural crest specifiers. Epigenetics 7:71-82
Scoles, Haley A; Urraca, Nora; Chadwick, Samuel W et al. (2011) Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples. Mol Autism 2:19
Meguro-Horike, Makiko; Yasui, Dag H; Powell, Weston et al. (2011) Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. Hum Mol Genet 20:3798-810
Schroeder, Diane I; Lott, Paul; Korf, Ian et al. (2011) Large-scale methylation domains mark a functional subset of neuronally expressed genes. Genome Res 21:1583-91
LaSalle, Janine M (2011) A genomic point-of-view on environmental factors influencing the human brain methylome. Epigenetics 6:862-9
Yasui, Dag H; Scoles, Haley A; Horike, Shin-Ichi et al. (2011) 15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain. Hum Mol Genet 20:4311-23
Leung, Karen N; Chamberlain, Stormy J; Lalande, Marc et al. (2011) Neuronal chromatin dynamics of imprinting in development and disease. J Cell Biochem 112:365-73
Hogart, Amber; Wu, David; LaSalle, Janine M et al. (2010) The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiol Dis 38:181-91
Gonzales, Michael L; LaSalle, Janine M (2010) The role of MeCP2 in brain development and neurodevelopmental disorders. Curr Psychiatry Rep 12:127-34

Showing the most recent 10 out of 26 publications