Beth Israel Deaconess Medical Center, Boston, MA
2010-2012
Principal Investigator: Matthew Anderson, MD, Ph.D.
Genetic Mouse Models of Autism
Recent studies of autism patients’ DNA revealed decreases or increases in the number of copies of specific genes. Two of these genes are unique in that they do not encode proteins, but instead only make strings of ribonucleic acid (non-coding RNA). The function of these recently discovered non-coding RNA molecules are completely unknown. Interestingly, protein coding sequences are highly homologous (80-90%) between mouse and man and most genes are shared between these two mammalian species. However, these two non-coding RNA genes cannot be found anywhere within the complete DNA sequence of the mouse genome. They are only found in humans and other primates, suggesting they might have a unique role in the primate brain. Dr. Anderson will explore the function of these two novel genes in human neuronal cells and will also introduce them into the mouse brain to assess their impact on autism-related behaviors and neuronal circuit function. These studies will discover the function of these two novel genes. The studies will also determine whether these genes can alter the behavior and neuronal circuit function to help establish an etiologic role in human autism.
Matthew Anderson Laboratory
Beth Israel Deaconess Medical Center, Boston, MA
2005-2010
Principal Investigator: Christopher Walsh, M.D., Ph.D.
Recessive Genes for Autism and Mental Retardation (Co-funded with The Simons Foundation)
Twin studies suggest that autism has a large genetic component; however, few potential autism susceptibility genes have been identified. The goal of this project is to use special genetic populations to map and identify autism spectrum disorders (ASD) genes to better understand their classification, pathogenesis, and potential treatments. Preliminary data show that the large families and patterns of consanguinity that characterize special populations such as the Arabic countries of the Middle East facilitate the recognition of recessively inherited neurological disorders. The investigator will identify appropriate pedigrees that show children with autism, and in which parents are related to one another, suggesting that recessively acting genes may be causing ASD in those families. He will then take advantage of this consanguinity to map and hopefully clone these recessive ASD genes. The investigator will focus on Arabic populations of the Middle East since these populations also show “founder mutations” which are restricted to certain groups, and which further facilitate precise gene mapping. This study may provide new insights into patterns of inheritance and genetic causes of autism spectrum disorders.
Christopher A. Walsh Laboratory
Children's
Hospital - Boston, MA
2004-2008
Principal Investigators: Michael E. Greenberg, Ph.D., Isaac Kohane, M.D, Ph.D., Louis M. Kunkel, Ph.D.
Genetic Studies of Autism Spectrum Disorders
This study will utilize genetics, bioinformatics, and neuroscience programs at Children's Hospital-Boston to address the genetic basis of autism spectrum disorders (ASD). One hypothesis of this study is that there are genetic variants that may predispose an individual to develop ASD, and that these genes can be identified by transmission disequilibrium testing (TDT) of candidate genes in pathways logically indicated based on gene expression and neuronal activity studies. Using TDT and trios (child with autism and their parents), and affected sib pairs (ASP) analysis, studies will be performed to look for association of ASD with candidate genes and for linkage peaks associated with ASD. Another hypothesis of this study is that there are differences in gene expression in the white blood cells of children with autism in comparison with normal children. Microarray analysis will be performed to study differences in gene expression in white blood cells of children with autism compared with that of normal children. Sparked by evidence that autism may be caused by defective synaptic maturation and the finding that activity-dependent gene transcription plays a role in synapse maturation, a third hypothesis of this study is that mutations of transcriptional regulators and their target genes may underlie some forms of autism.
Michael Greenberg
Isaac Kohane
Louis Kunkel
Children's Hospital - Boston, MA
2009-2010
Principal Investigator: Isaac Kohane, M.D, Ph.D.
Small RNAs and Editing in Autistic Brains
Autism is a common neurodevelopmental disorder characterized by a spectrum of social deficits, communication impairments, stereotyped interests, and repetitive behavior. Twin and family studies provide substantial evidence that autism is among the most heritable complex disorders, but the molecular mechanism underlying the majority of autism cases remains unknown. Understanding the genetic basis of autism is needed to improve diagnosis and provide critical targets for intervention and prevention. The long-term goal of this research is to characterize the genetic and molecular mechanisms that predispose to autism spectrum disorders (ASD). The objective of this research project is to investigate the involvement of RNA-mediated post-transcriptional regulation in ASD. MicroRNAs (miRNAs) and small nucleolar RNAs (snoRNAs) are gaining increasing recognition for their key role in orchestrating complex brain development. Both molecules are heavily involved in A-to-I editing, which is crucial for appropriate animal behavior. As the regulators affect multiple transcripts, each subject to sequence variation of its own, the investigators hypothesize that alterations in these upstream regulatory mechanisms can account for the broad phenotypic spectrum and complex inheritance pattern observed in autism. Isaac Kohane
Massachusetts Institute of Technology, Picower Institute for Learning and Memory, Cambridge, MA
2009- 2010
Principal Investigator: Damon Page, Ph.D.
MAPK3 as a Chr 16p11.2 Autism Candidate Gene
The chromosomal region of 16p11.2 has emerged from genetic screening in humans as a significant susceptibility locus for ASD. This interval contains 25 genes; however, the link between these genes and the symptoms of ASD is not clear. This project seeks to bridge this gap in our understanding by investigating the role of candidate genes from the 16p11.2 region in the development of brain and behavior, using the mouse as a model system. The first candidate gene that Dr. Page will focus on is MAPK3. He selected this gene as a candidate for the following reasons: 1) He had previously found that ERK, the Drosophila homologue of MAPK3, influences regionalized growth in the embryonic brain by controlling proliferation of specific populations of neural stem cells in response to activation of the receptor tyrosine kinase EGFR in these cells (Page, 2003), 2) MAPK3 is known to act in the PTEN/PI3K pathway to influence a variety of cellular processes relevant to growth (Cully et al., 2006). Dr. Page has found that haploinsufficiency for Pten leads to brain overgrowth as well as social behavioral deficits (Page et al., 2009), two phenotypes relevant to ASD. And, 3) MAPK3 acts in several additional pathways that have been implicated in ASD pathogenesis, including: Serotonin (Launay et al., 1996), Oxytocin (Blume et al., 2008) and IL-6/immune signaling (D'Arcangelo et al., 2000). Dr. Page’s studies indicate that Pten intersects with these pathways in the developing brain. Thus, the possibility that MAPK3 might act as an intermediary across these pathways is one worth exploring. As an initial investigation of the function of Mapk3 in ASD-relevant endophenotypes, Dr. Page will make use of assays of social approach behavior and brain growth.
Damon Page
Princeton University , Princeton , NJ
2008-2011
Principal
Investigators: Arnold J. Levine, Ph.D. & Daniel A. Notterman,
MD
Autism
and Single Nucleotide Polymorphisms in the IGF Pathway (Co-funded
with
The
Simons Foundation)
This
project's goal is to test the frequencies of single nucleotide
polymorphisms (SNPs) in selected genes that populate the
IGF-1, mTor and p53 interrelated signal transduction pathways
in individuals with autism spectrum disorder. The IGF-1,
mTor and p53 networks are known to act in the central nervous
system (CNS) and regulate cell growth and size, dendrite
formation, metabolic capabilities, glucose and amino acid
use, stress and cell/DNA damage. It has become apparent
that there are connections between the IGF-1-PI3K-AKT (cell
growth, anti-apoptotic), mTor (glucose and amino acid sensing,
autophagy control, metabolic regulation) and the p53 (stresses
of many kinds-oxidative, hypoxia, DNA damage, etc leading
to apoptosis and senescence) pathways. These three inter-related
networks play a role in cancer; they are involved in diabetes
and glucose utilization by cells, and they affect longevity.
Several lines of evidence suggest that this same critical
set of genes can act in the CNS to contribute to autism.
For example, 60% of individuals with either TSC-1 or TSC-2
mutations have autism; some individuals with mutations in
the PTEN gene develop autism, and a knock-out of the PTEN
gene activity in the CNS of mice alters the structure of
the CNS and results in behavioral abnormalities in these
mice. Thus, the genes in these networks are interesting
candidates whose alleles might contribute to autism or ASD.
Initially, the PIs will examine possible increased frequencies
of SNPs and haplotypes from each gene separately. Later,
combinations of SNPs, haplotypes and genes will be examined
for enhanced frequency in the autistic group. When the PIs
are confident that a SNP or a haplotype is contributing
to the autistic phenotype, they will explore the molecular
effect of the SNP. Looking for polymorphisms in these candidate
genes will complement other ongoing studies to track down
mutations that contribute to autism spectrum disorder.
Arnold
Levine
Daniel Notterman
University of Cambridge Autism
Research Centre, Cambridge , UK
2004-2011
Principal Investigator: Simon Baron-Cohen, Ph.D.
A Genetic Study of Mathematical Talent and Asperger's Syndrome
Autism spectrum disorders often involve impaired empathy and intact or talent in systemizing. Research has suggested a link between talent in systemizing and the likelihood of autism in a family. This suggests that one of the genes involved in autism may be the gene (or genes) that underlie systemizing talent. This research attempts to identify genes associated with a well-defined example of systemizing talent, mathematical giftedness. Researchers will obtain DNA from large families where there are many gifted mathematicians, and will re-test any significant regions of the DNA in detail in a sample of mathematicians vs. non-mathematicians. Researchers are also studying DNA of people with Asperger Syndrome (AS) to see if the genes for systemizing are implicated in the genes for AS. Genetic research may improve early diagnosis of autism spectrum conditions.
Autism Research Centre
Simon Baron-Cohen
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