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I am doing research on inherited risk of Autism Spectrum Disorders(ASD) due to common Copy Number Variants(CNVs) One of the mutations is the 'CC' variant of Rs1858830 in the promoter region of the MET gene. (http://www.snpedia.com/index.php/Rs1858830)

After digging a bit deeper I found that hepatocyte growth factor is a pretty ubiquitous compound in the body and it's necessary for growth/repair of many tissues, namely the liver and digestive tract. I am trying to separate the direct causal effect of the mutation itself from the effects it has on other tissue which may themselves have an effect on ASD risk.

My question comes from a study which measured reduced serum HGF levels in autistic children with this mutation. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694825/)

I am confused about the implied causal effect of the 'CC' variant on HGF levels even though it is merely the ligand for the MET gene? Please help me understand where in the gene signalling process does HGF come in, what does it do, what proteins are transcribed by the MET gene, and how this mutation effects the transcription of these proteins.

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HGF is the ligand for Met, which is a membrane receptor involved in multiple transduction pathways. Gene ID 4233 we're looking at a single gene product for MET.

If we're just reading through the wikipedia page for c-Met, when HGF binds to Met, it activates the tyrosine kinase activity of Met. Met recruits Gab1, and this complex mediates interactions with Ras, P13K, ß-catenin.. not just pathways associated w/ Autism, but also associated with invasive growth cancers. An interesting note about the C allele, it's associated with decreased Met transcription. Quoting a recent article,

The present morphological and functional studies have revealed a highly novel mechanism conferred by MET receptor signaling, which we show serves a pleiotrophic role in controlling both neuronal and spine morphology, and the time course of glutamatergic synapse maturation on CA1 hippocampal neurons. Such findings are consistent with the possibility that mistimed maturation of glutamatergic synapses underlie aberrant function of neural circuits that are enriched in MET during development.

Source

So the critical results from the same study showed that when Met got knocked down or deleted, we saw maturation of neural tissue. So now, if i'm thinking about Met and HGF, your article notes that HGF is decreased in autism brains. If we (1) need HGF for Met function, and (2) ASD may be attributed to decreased Met function, and (3) the C allele decreases Met levels, we're basically looking at a system that's modulating for ASD.

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  • $\begingroup$ Thank you very much for your thorough answer. Could you explain what you mean by "modulating for ASD"? I'm not completely sure what you meant by that, as I see two possibilities: 1.) HGF production is downregulated due to a reduced binding with MET $\endgroup$ – ASD Researcher Jul 13 '15 at 22:13
  • $\begingroup$ Basically all I was saying is the system of circumstances was pushing toward a state that would make ASD more likely. For the actual reason HGF level become reduced I'm actually not too informed! $\endgroup$ – CKM Jul 13 '15 at 22:21
  • $\begingroup$ 2.)HGF is the limiting reactant in the pathways you mentioned above. If you would like some context, I am investigating the effect of supplemental HGF in an attempt to normalize dendritic spine outgrowth and recover cognitive function in this particular mutation. I would also like to know what you think of the impact on cell growth/differentiation in other tissue/is this an issue of merely HGF shortage or are the effects of this mutation mostly downstream of the ligand binding? $\endgroup$ – ASD Researcher Jul 13 '15 at 22:23
  • $\begingroup$ I've read through some articles where Stat3 and c-Src play a role downstream of c-Met, where they found Stat3 and c-Src in the promoter of HGF increasing HGF transcription. If it's a decrease in relative c-met levels that's heavily impacting Stat3/Src mediated HGF transcription, it could be that the actual issue is with the levels of c-Met. $\endgroup$ – CKM Jul 13 '15 at 22:47
  • $\begingroup$ One more question: The mutation itself is a change of base from a Guanine to a Cytosine. Do promoter region mutations generally mean RNA polymerase cannot fully attach itself to the promoter region resulting in reduced replication of the associated protein? When you say "decrease in c-met" do you actually mean there is less c-Met protein being produced? $\endgroup$ – ASD Researcher Jul 13 '15 at 23:08

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