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. 2008 Jun;1(3):159-68.
doi: 10.1002/aur.27.

Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder

Daniel B Campbell  1 , Chun Li, James S Sutcliffe, Antonio M Persico, Pat Levitt
Affiliations

Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder

Daniel B Campbell et al. Autism Res. 2008 Jun.

Abstract

A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5' promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case-control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12-3.31) for genotype TT and 2.42 (95% CI: 1.38-4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.

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Figures

Figure 1
Figure 1
Gene structure, genotyped markers and linkage disequilibrium (LD; in r2) block structure of the five genes involved in regulation of MET receptor expression and signaling. Each gene is represented 5′>3′. Exons are indicated by boxes.
Figure 2
Figure 2
Associations of PLAUR and SERPINE1 with ASD in multiplex families. Plotted are -log10 P values for over-transmitted alleles (points) and global LD block analyses (lines). (a) The PLAUR promoter variant rs344781 allele T (marker 3; P=0.004), the rs344772-rs344780-rs344781-rs344783 LD block (markers 1−4; P=0.037) and the rs344780-rs344781 LD block (markers 2−3; P=0.0002) demonstrated significant association in multiplex, but not simplex, families. (b) The SERPINE1 marker rs13238709 allele C (marker 5; P=0.041), the rs2227631-rs2070782-rs7242-rs13238709 LD block (markers 1, 3, 4 and 5; P=0.004) and the rs2070782-rs7242-rs13238709 LD block (markers 3−5; P=0.0008) were associated with ASD in multiplex, but not simplex, families.
Figure 3
Figure 3
Functional analysis of the PLAUR promoter variant associated with ASD. Insertion of a 500-bp PLAUR promoter fragment containing either variant of rs344781 increased transcription ∼6-fold compared to the promoterless vector control following transfection of human embryonic kidney (HEK) or mouse neuronal (SN56) cell lines. The T allele-containing fragment exhibits greater induction in the neuronal cell line compared to the C allele (P=.044, paired t-test), but no difference in the epithelial cell line. Error bars represent SEM (n=5).
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