The clinical manifestation of autism spectrum disorder (ASD) is highly complex and heterogeneous, with medical and mental health disruptions beyond the three core behavioral criteria used for diagnosis (social behavior, communication, restricted interests/repetitive behavior). Co-occurring medical conditions, such as gastrointestinal dysfunction (GID), often are overlooked when designing research strategies to understand the mechanisms underlying the expression of ASD. The developmental mechanisms through which such diverse symptoms arise are unknown, but we hypothesize that some autism vulnerability genes encode pleiotropic molecules that participate in the development and function of multiple systems. This unique hypothesis is based on our discovery that the gene encoding the tyrosine kinase receptor MET carries a 5'common polymorphism (C) that disrupts transcription. In total, 6 independent cohorts from 3 different laboratories have identified this and one other variant (intron 1) that is enriched in ASD. MET plays a role in brain wiring and GI epithelial cell repair. Our recent retrospective study in 200+ AGRE families demonstrated that the C allele is represented in 65% of the cases with co-occurring GID and ASD, compared to 58% in ASD alone and 47% in the general population. This R21 initiative proposes a prospective study at Children's Hospital of Los Angeles/USC and the Monroe Carell Jr Children's Hospital at Vanderbilt University.
In Aim 1, we will characterize GID in pediatric populations with and without ASD. The study population will be characterized in detail with both a standardized instrument for diagnosing functional GI disorders in children, the Questionnaire on Pediatric Gastrointestinal Symptoms, and with the clinical acumen of an experienced pediatric gastroenterologist. Nutritional information also will be collected to determine whether there are patterns of dysfunction that correlate with dietary and nutritional status. The in-depth characterization of GID in ASD will provide unique epidemiological descriptions of the study population that may reveal specific patterns of GI conditions within the +ASD/+GID group.
In Aim 2, we will connect the genetic risk findings with biological changes that may account for GI and brain dysfunction. We will genotype all participants at the two ASD- associated MET loci. We also will quantify MET protein in the same study population in peripheral monocytes, which is the primary blood cell type that expresses MET. We have ascertained gut biopsies from an additional group of +ASD/+GID subjects and will utilize these tissues to directly measure pan-MET and phospho-MET protein levels.

Public Health Relevance

The research proposal will directly investigate relationships between co-occurring medical conditions and ASD, testing a biological hypothesis regarding disruption of MET signaling as a common theme. The studies will provide insight into patient stratification and biomarker identity that may improve diagnosis and treatment.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-B (A1))
Program Officer
Kau, Alice S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Anatomy/Cell Biology
Schools of Medicine
Los Angeles
United States
Zip Code
Eagleson, Kathie L; Xie, Zhihui; Levitt, Pat (2017) The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism. Biol Psychiatry 81:424-433
Zamora, Irina; Williams, Marian E; Higareda, Marcia et al. (2016) Brief Report: Recruitment and Retention of Minority Children for Autism Research. J Autism Dev Disord 46:698-703
Aldinger, Kimberly A; Lane, Christianne J; Veenstra-VanderWeele, Jeremy et al. (2015) Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder. Autism Res 8:771-81
Bone, Daniel; Lee, Chi-Chun; Black, Matthew P et al. (2014) The psychologist as an interlocutor in autism spectrum disorder assessment: insights from a study of spontaneous prosody. J Speech Lang Hear Res 57:1162-77
Gorrindo, Phillip; Lane, Christianne Joy; Lee, Evon Batey et al. (2013) Enrichment of elevated plasma F2t-isoprostane levels in individuals with autism who are stratified by presence of gastrointestinal dysfunction. PLoS One 8:e68444
Gorrindo, Phillip; Williams, Kent C; Lee, Evon B et al. (2012) Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res 5:101-8