Investigating a New Loss-of-Function Model for the Xlr3 Gene Family

University Of Connecticut Storrs, Storrs-Mansfield CT

Investigators

Abstract

PROJECT SUMMARY According to the Centers for Disease Control and Prevention (CDC), about 2.25% of children in the U.S. have been diagnosed with Autism Spectrum Disorder (ASD). The economic burden of ASD in the U.S. for 2015 has been estimated to be $268 billion in direct medical, direct non-medical, and productivity costs. Etiological studies over the past 2-3 decades implicate both genetic and environmental causes for the occurrence of ASD, but the relative contribution of each of these factors is controversial. Over the last two decades and across the globe, several genetic and epidemiological studies involving thousands of individuals and families with ASD have been performed to identify the genetic factors contributing to ASD susceptibility. Despite this intensive effort, we still understand relatively little about the events during fetal development that bring about autism in young children. Furthermore, diagnostic biomarkers and therapeutic targets for the disorder remain elusive. An understudied aspect of ASD occurrence is that it is much more prevalent among boys than girls. The bias in favor of boys is estimated to be about 4:1, but there is, as of yet, no explanation for the sex bias. Our lab has focused on the theory that the sex bias may be caused by parent-of-origin differences in epigenetic factors on the X chromosome, a.k.a. genomic imprinting. About twelve years ago we identified the first imprinted gene cluster on the mammalian X chromosome, members of the Xlr3 and Xlr4 gene family, which are expressed predominantly from the maternal X chromosome during brain development. The expression of the Xlr3 and Xlr4 genes have been shown to be disrupted in mouse models of neurological disease. Our functional investigation of these genes implicates this gene as a chromatin associated factor involved in repression of gene expression. In this application, we propose to utilize a transgenic mouse model we have created that targets Xlr3 expression. Using a scheme of transcriptome (gene expression) profiling, we propose to examine the function of these genes in gene regulation, neurodevelopment and behavior.