Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder.
MET-pathway genes beyond MET itself—especially PLAUR—additively increase ASD risk, so genetic counselors should screen the full panel.
01Research in Context
What this study did
The team looked at genes in the MET signaling pathway. They wanted to see if several genes together raise autism risk.
They tested DNA from people with autism spectrum disorder. The study checked many variants, not just the famous MET gene.
What they found
Variants in PLAUR and other MET-pathway genes added extra risk. One PLAUR promoter change nearly doubled the chance of ASD.
The effect was strongest when several pathway variants showed up together.
How this fits with other research
Ohashi et al. (2021) later showed most single gene tests give clear answers in only 1 out of 10 non-syndromic cases. That finding tempers this 2008 result: MET-pathway markers help, but they rarely give yes-or-no answers.
Torske et al. (2020) extended the idea by using a genome-wide autism score. They linked higher total genetic load to everyday executive problems in clinic-referred kids. Their work moves from one pathway to the whole genome.
Q et al. (2023) shifted the timeline earlier. They found four gene transcripts in cord blood that predict autism by age three. Together these papers trace a line: single pathway → whole genome → newborn expression.
Why it matters
You can’t treat genes, but you can use the knowledge. When a child carries MET-pathway variants, watch for early signs and refer sooner. Tell families the risk is real yet small, and stress that therapy still drives progress. Keep an eye on siblings too—they may share the same markers.
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02At a glance
03Original 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.
Autism research : official journal of the International Society for Autism Research, 2008 · doi:10.1002/aur.27