Distinct Genetic Risk Based on Association of MET in Families With Co-occurring Autism and Gastrointestinal Conditions

Vanderbilt University, 8114 MRB3, 465 21st Ave South, Nashville, TN 37232, USA.
PEDIATRICS (Impact Factor: 5.3). 04/2009; 123(3):1018-24. DOI: 10.1542/peds.2008-0819
Source: PubMed

ABSTRACT In addition to the core behavioral symptoms of autism spectrum disorder, many patients present with complex medical conditions including gastrointestinal dysfunction. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, we hypothesized that association of the autism spectrum disorder-associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions.
Subjects were 918 individuals from 214 Autism Genetics Resource Exchange families with a complete medical history including gastrointestinal condition report. Genotypes at the autism spectrum disorder-associated MET promoter variant rs1858830 were determined. Family-based association test and chi(2) analyses were used to determine the association of MET rs1858830 alleles with autism spectrum disorder and the presence of gastrointestinal conditions.
In the entire 214-family sample, the MET rs1858830 C allele was associated with both autism spectrum disorder and gastrointestinal conditions. Stratification by the presence of gastrointestinal conditions revealed that the MET C allele was associated with both autism spectrum disorder and gastrointestinal conditions in 118 families containing at least 1 child with co-occurring autism spectrum disorder and gastrointestinal conditions. In contrast, there was no association of the MET polymorphism with autism spectrum disorder in the 96 families lacking a child with co-occurring autism spectrum disorder and gastrointestinal conditions. chi(2) analyses of MET rs1858830 genotypes indicated over-representation of the C allele in individuals with co-occurring autism spectrum disorder and gastrointestinal conditions compared with non-autism spectrum disorder siblings, parents, and unrelated controls.
These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent research has established that many children and adult diagnosed with autism experience gastrointestinal symptoms. Furthermore, research has demonstrated that gastrointestinal symptoms can impact drug availability and absorption. In this paper we explore the presence of gastrointestinal symptoms in autism and put forth a call for a formal evaluation of the potential relationship between gastrointestinal symptoms and psychotropic medication effectiveness in individuals with autism.
    The Journal of Clinical Pharmacology 05/2014; 54(10). DOI:10.1002/jcph.324 · 2.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastrointestinal disturbances (GID) are frequently reported in children with autism spectrum disorders (ASD). Recently, mounting evidence suggests that there may be a genetic link for autism with gastrointestinal disturbances.We aimed to investigate whether there were any association between the -1438A/G, 102T/C and His452Tyr polymorphisms of the serotonin 2A receptor gene (5-HT2A) in Egyptian children with ASD and GID. Eighty children with autistic disorder and 100 healthy control children were examined. -1438A/G, 102T/C and His452Tyr polymorphisms of 5-HT2A were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant increase of the G allele and the GG genotype of the -1438A/G polymorphism was observed in children with autism than control, but there were no significant differences in the frequencies either of the 102T/C genotype or His452Tyr genotype between the two groups. There was a significant increase of homozygote A allele of the -1438A/G and CC genotype of the 102T/C polymorphism in ASD children with GID. This study supports the possible involvement of the 5-HT2A receptor in the development of ASD and associated GID.
    Research in Developmental Disabilities 11/2014; 36. DOI:10.1016/j.ridd.2014.10.023 · 3.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorder (ASD) results from interactions of genetic and environmental factors. The MET proto-oncogene has been identified as a candidate gene for autism susceptibility, and is implicated in neurodevelopment and social brain circuitry. Here, we describe the first case of a familial mutation of MET, consisting of an interstitial genomic deletion removing exons 12 through 15, causing a frameshift and premature stop codon, with evidence of nonsense-mediated mRNA decay. On the other allele, patients carried the C allele of the MET promoter rs1858830 polymorphism, known to decrease MET expression and previously associated with autism susceptibility. The heterozygous mutation was associated with autism in one patient, and language and social impairment in a sibling. Our observations delineate the phenotypic spectrum associated with a clearly defined, very likely complete loss of function mutation of MET. Incomplete penetrance in this family was consistent with MET as a partial susceptibility gene for ASD. Implication of MET in normal and pathological brain development opens new perspectives for understanding the pathophysiology of autism and for eventual therapeutical clues. Autism Res 2014, ●●: ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
    Autism Research 06/2014; 7(5). DOI:10.1002/aur.1396 · 4.53 Impact Factor