Disruption of cerebral cortex MET signaling in autism spectrum disorder

Abstract

Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD.

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

“…42 These tissue samples largely overlap with those employed in our recent study of the MET pathway. 5 Clinical and demographic information, family history and autopsy reports were obtained from the Autism Tissue Program web site (www. atpportal.org) and are summarized in Table 3.…”

“…This strategy can indeed promote a better understanding of single-gene contributions to complex disorders, as recently demonstrated for the MET gene in autism. 4,5 Several lines of evidence suggest that autism should be viewed as a multiorgan systemic disorder with a prenatal onset. On one hand, autism does not solely affect the central nervous system (CNS), despite encompassing obvious neurodevelopmental components: systemic signs and symptoms include macrosomy, 6 excessive intestinal permeability and nonspecific enterocolitis, [7][8][9] immune dysreactivity 9 and renal oligopeptiduria.…”

“…32 Still, the presence of a significant genetic association in two different ethnic groups, coupled with the functional involvement of PRKCB1 in many pathophysiological processes potentially underlying disease-related endophenotypes, spur interest into additional studies of PRKCB1 in autism. In accordance with the strategy outlined above and previously employed successfully with the MET gene, 4,5 this study was designed to replicate the initial genetic findings in an independent sample and to extend these studies by (a) assessing PRKCB1 gene expression in postmortem temporocortical gray matter (BA41/42) from 11 pairs of ASD patients and sex-, age-, and postmortem intervalmatched controls; (b) correlating PRKCB1 gene expression with PRKCB1 genotypes in these postmortem brain samples and (c) assessing the functional consequences of dysregulated PRKCB1 gene expression using genomewide expression array technology. Our results confirm the existence of a significant association between PRKCB1 gene variants and autism, describe for the first time an association with the biochemical endophenotype defined by enhanced urinary peptide excretion rates, detect a significant reduction of PRKCB1 mRNA and protein levels in postmortem autistic brains, reveal a dysregulation of gene expression patterns delineating a possible compensatory adjustment aimed at limiting an ongoing immune dysreactive process and identify a lack of downregulation in gene expression as the most likely functional correlate of PRKCB1 alleles conferring autism vulnerability.…”

Autism genetics: Methodological issues and experimental design

“…We have identified RELN as a new vulnerability gene [77,78], which currently enjoys the strongest supporting evidence of involvement in autism among all vulnerability genes [79]. Another vulnerability gene, MET, was identified by Campbell and Levitt collaborating with our group for the genetic studies involved in this project [80,81]. In addition, we have identified other new vulnerability genes and confirmed associations initially reported in other samples for several genes, including ADA [82], APOE [83], HOXA1 [84,85], ITG-B3 [86], PON1 [87], PRKCB1 [88], SLC6A4 [89,90], SLC-25A12 [91].…”

When linkage signal for autism MET candidate gene

“…The expression of MET transcript and MET receptor tyrosine kinase protein was shown to be reduced in postmortem brains of individuals with autism compared to age-and gender-matched controls. 4 A number of genetic mechanisms may contribute to the decreased expression of MET in autism. Significant association of the MET promoter rs1858830 C allele was first reported in a 204 family Italian cohort and replicated in a 539 family US cohort.…”