MET

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MET

Met is a receptor tyrosine kinase that is expressed during the mouse development in the areas of the brain involved in social behavior and emotional regulation. Previous studies suggest that when MET receptors are activated, the development and maturation of social behavior and emotional regulation are changed. In addition, changes in the transcription of the MET gene via the promoter variant rs1858830 C allele or of another marker on the MET gene, have been significantly associated with Autism Spectrum Disorders. MET transcript and MET protein are decreased 2 fold in postmortem brains of individuals with ASD as compared to typically developing individuals. MET receptor tyrosine kinase also has a role in Gastrointestinal repair, which could explain why gastrointestinal problems occur more frequently in those with ASD than in the typically developing population. It has been shown in the mouse forebrain that there is an enrichment of Met expression in projection neurons of the cerebral cortex, hippocampus, and amygdala especially during synapse formation and pruning. The circuits in these brain regions control the striatum, thalamus, subcortical limbic structures, and the integration of information across cortical areas, thus affecting the core social, communication, and behavioral flexibility domains.1


The MET biological pathway, which is composed of its is the only known ligand hepatocyte growth factor, the proteins that mediate receptor signaling, and the proteins that mediate receptor signaling can be influenced by all of these mechanism of heritable risk variants, de novo mutations and copy number variations, and genetic and environmental modifiers of core phenotypes and associated medical conditions.1 Two genes, PLAUR and SERPINE1 that are involved in the MET signaling pathway are associated with increased ASD risk, and each mRNA exhibits altered expression in the postmortem cerebral cortex of individuals with ASD compared to controls. In both multigenic and syndromic ASD, Pl3K signal disruption occurs. However, the MET-regulating genes PLAUR and SERPINE1 are only found in multiplex families and thus linked to multigenic, idiopathic ASD. The broader autism phenotype is found to a far greater extent in parents from multiplex rather than simplex families, suggesting that heritable, rather than de novo mechanisms for ASD expression occur in multiplex families. 2

Furthermore, the MET/Pl3K pathway is highly vulnerable to environmental perturbations. The normal level of binding of the transcription factor SP1 in the ERK/Pl3K pathway is reduced by the ASD-associated rs188830 C allele. 2



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References

1. Campbell DB et. al. Association of MET with social and communication phenotypes in individuals with autism spectrum disorder.Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 22. PMID 19548256

2. Levitt P. et. al. The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders.J Clin Invest. 2009 Apr;119(4):747-54 PMID 19339766