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Scientific Abstract from:
William McMahon, M.D.
University of Utah
The Utah Autism Project


Overall Description

This renewal proposes three components and three cores to extend our studies of phenotypes associated with autism. The Immune Components will address 4 specific aims: 1) investigate the interaction between serotonin and immune dysregulation; 2) characterize the specificity and autoreactivity of T cells and antibodies in subjects with autism; 3) identify relationships between autoreactive T cells and/or antibodies and increased head size and other brain anomalies identified in the Neuroimaging component; 4) perform microarray analysis on RNA isolated from PBMCs of autistic vs. control children to determine the altered genes. These genes may then be studied in the pedigrees identified by the Genetics Component. The Genetics Component will collect DNA and clinical information on affected cases and relatives (including intermediate phenotypes: broader autism phenotype, head circumference, serotonin levels, and stored serum for immune phenotype identified by the Immune Component). Assessments will be done on five extended Utah kindreds already identified through the Utah Population Data Base, and on two new extended pedigrees to be identified through a new UPDB search of 800 new autism cases identified through surveys and the State Health Department and University of Utah clinics. A genome scan will be done using the University of Utah Department of Human Genetics laboratory. Pedigrees will be analyzed using the clinical phenotype and intermediate phenotypes to map susceptibility loci. Five candidate genes under linkage peaks and/or identified by the Immune Component will be genotyped using SNPs. DNA, whole blood (for future serotonin), and serum (for future immune phenotyping) will be stored on the 800 new autism cases and their parents for future family based association studies. The Neuroimaging Component will study persons with autism, employing structural and diffusion tensor imaging studies to address the following specific aims: 1) describe longitudinal changes in structural brain volumes and their relationships to changes in clinical phenotypes; 2) describe relationships between brain structure and white matter integrity. Subjects will overlap with those studied by the Immune Component.

Project I

Principal Investigator: Robert S. Fujinami, PhD.

The etiology and pathogenesis of autism is still unknown. This developmental disease is acknowledged as a syndrome having a broad range of symptoms. It appears that genetics play a major role in the development of this disease. Two lines of evidence support this. First, twin studies have shown concordance rates between 36% to 91% for monozygotic twins and 0% to 30% for dizygotic twins, depending on the criteria used to define autism. Second there is evidence for an association with autism and a region on human chromosome 6 encompassing the major histocompatibility complex (MHC) that includes HLA class I and class II, and some of the complement components, including C4B. Since concordance rates in monozygotic twins are not 100%, this implies that other factors play a role in the development of autism or are responsible for different subtypes of this disease. Elevated serotonin levels are a consistent finding in autism. Similarly, it appears that the immune response and/or immune regulation in autistic subjects is altered versus control subjects. These immune aberrations often present as a decreased lymphoproliferative response to mitogens and immune reactivity to central nervous system (CNS) proteins. Genetic predisposition (elevated serotonin levels) and /or environmental agents such as viral infections or exposure to toxins in utero or early in life could be responsible for the immune dysregulation. Immune responses against CNS proteins during development could lead to CNS changes that affect behavior and social development later in life.

First, we propose to investigate the role of serotonin in inducing dysregulation of the immune response. Second, we will examine the specificity and autoreactivity of T cells and antibodies present in children with autism. Third, we plan to determine whether immune effector cells and antibodies induce or mimic CNS features often observed in autistic subjects such as hippocampal and mammillary body changes. Fourth, we propose to perform microarray analyses on RNA isolated from peripheral blood mononuclear cells (PBMC) of autistic children versus control subjects. Determining what genes are altered and identifying their chromosomal positions may lead to additional loci that contribute to this disease.

Project II

Principal Investigator: Hilary Coon, Ph.D.
Co-Investigators: William McMahon, M.D., and Mark Leppert, Ph.D.

The Genetics Component will search for susceptibility genes for autism using extended pedigrees identified through the Utah Population Database (UPDB). We have already identified five pedigrees with 3-7 affected members and large sibships, and have DNA on one pedigree with seven affected cases. UPDB searches for two new pedigrees will be performed using 800 new cases of autism ascertained from four sources. DNA from these 800 cases and their parents will be banked for future family-based association studies. Serum and whole blood will also be banked for future serotonin and immune assays. These cases will also provide approximately 40 new sib pairs for network-wide studies, and a pool of subjects for network-wide regression studies. Within members of identified extended pedigrees, we will collect phenotypic data on traits that have shown promise in preliminary data as intermediate phenotypes for autism. An intermediate phenotype occurs in unaffected and affected family members, and may serve as a marker for carrier status of susceptibility genes for autism. These traits may help us to identify specific susceptibility genes associated with particular intermediate phenotypes. Preliminary studies suggest several promising intermediate phenotypes, including the Broader Autism Phenotype (BAP; mild clinical symptoms in communication, social and behavioral domains), serotonin levels from blood, and head circumference. Immune phenotypes will be identified by the Immune Component; serum for immune assays will be stored on all subjects. A genome scan will be done using the laboratory of Dr. Mark Leppert, University of Utah Human Genetics Department. Pedigrees will be analyzed using the clinical phenotype and intermediate phenotypes to map susceptibility loci. Four candidate genes under linkage peaks will be genotyped using SNPs. Budget resources will also be reserved to SNP type the best candidate gene identified through microarray studies in the Immune Component, for a total of five candidate genes.

Project III

Principal Investigator: Janet E. Lainhart, M.D.
SubContract PIs: Erin Bigler, Ph.D., Brigham Young University; Andrew Alexander, Ph.D., University of Wisconsin

Autism is a severe lifelong developmental disorder that affects approximately 1.6/1000 individuals. What goes awry in brain development in autism is not known. As a result, there is no treatment targeting the pathologic process underlying autism and no way to prevent the disorder.

The goal of component III is to define morphometric brain abnormalities that are specific to autism and to describe how the abnormalities are related to each other and to clinical features of autism. To accomplish this goal, we will collect cross-sectional and longitudinal morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) data on 72 children and adults with autism and 54 controls, with a special focus on the temporal lobe. We will describe longitudinal changes in total and regional brain volumes in autism, including gray and white matter and regional temporal lobe volumes. Within individuals and study groups, we will describe how abnormalities in volume and size relationships of temporal lobe structures are related to abnormalities in the integrity and anatomy of white matter tracts on DTI.

Last Updated Date: 11/30/2012
Last Reviewed Date: 11/30/2012
Vision National Institutes of Health Home BOND National Institues of Health Home Home Storz Lab: Section on Environmental Gene Regulation Home Machner Lab: Unit on Microbial Pathogenesis Home Division of Intramural Population Health Research Home Bonifacino Lab: Section on Intracellular Protein Trafficking Home Lilly Lab: Section on Gamete Development Home Lippincott-Schwartz Lab: Section on Organelle Biology