Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. Although research on ASDs has implicated multiple genes in pathogenesis, etiology for the majority of cases remains unknown. In the context of profound etiological and phenotypic complexity, one strategy to seek insight into risk and pathogenesis is to stratify a heterogeneous population based on a prominent feature, resulting in increased homogeneity within population strata. One such feature is gastrointestinal dysfunction (GID), which is present in a subpopulation of individuals with ASDs. A previous report demonstrated signal enrichment for an ASD risk variant in the MET gene specifically in individuals with co-occurring ASD and GID (ASD-GID), suggesting shared genetic risk for both the nervous and gastrointestinal systems due to pleiotropic expression of MET. The objectives of the current studies were to examine relationships between proposed causes of GID and GID outcomes in ASD; to investigate clinical and biological features specific to ASD-GID; and to study the biological roles played by Met in the gastrointestinal system of conditional knockout mice. Children with ASDs, with and without GID, as well as children with GID only, donated a blood sample and were assessed for language and social function, dietary habits and GID status. Met conditional null mice, lacking Met signaling capacity in the GI epithelium, were assessed for repair ability in response to acute epithelial injury. In children with ASDs, no association was found between dietary habits or medication status, and GID outcome. A significant fraction of children with ASD-GID had no expressive language, and had greater social impairment, compared to children with ASD only or GID only. Prevalence of the MET risk variant was increased in the ASD groups. The possibility that children with ASD-GID are more severely impacted is supported by data demonstrating significant elevation of a marker of oxidative stress specifically in this group. In the animal model studies, Met conditional null mice demonstrated impaired healing capacity in response to GI injury. These findings have important implications both for improving clinical care of children with ASDs and co-occurring GID, and for further understanding risk and pathogenesis in a subpopulation of individuals with ASDs.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11262011-180509 |
| Date | 08 December 2011 |
| Creators | Gorrindo, Phillip |
| Contributors | Karoly Mirnics, James Sutcliffe, Nancy Brown, Pat Levitt |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-11262011-180509/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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