One Gene to Regulate Them All (or, at least many of them)

I have recently written about the complexities of the underlying genetics of autism, including issues of gene regulation. That particular article focused on RNA regulation through methylation. Now there is more evidence for the importance of RNA regulation in Nature. The CPEB-4 protein is involved in the addition of the poly-A tail to mRNAs, and there is a version that specifically regulates this in genes connected to autism.

Each mRNA–which allows the genes for proteins to be turned into those proteins–has a tail of adenosines (one of the nucleotides) added to it after it is transcribed from the DNA. This is important because when the mRNA is translated into a protein, a nucleotide is removed from the end of the RNA. The longer the tail, the more proteins can be made. If only short tails can be produced, there will not be enough proteins produced. CPEB-4 seems to be involved in regulating the length of the poly-A tail.

As already mentioned, things in the cell are complex. In learning more about this gene, I have learned that the protein, cytoplasmic polyadenylation element binding protein, is found in the dendrites and cell body of neurons, but that “treatment of neurons with ionotropic glutamate receptor agonists causes CPEB4 to accumulate in the nucleus. ” Here we again see a gene/protein related to autism connected to glutamate. Stress conditions in the brain–low oxygen or glucose, for example–cause CPEB4 to be sent from the cytoplasm to the nucleus, where they cannot do their job of regulating poly-A in the cytoplasm.

As noted, the CPEB4 gene seems to be central, but that doesn’t mean we should necessarily see mutations in it connected to autism. There could be mutations in the gene(s) for the ionotropic glutamate receptor, or in the gene(s) for glutamate production, or in some other regulator of CPEB4. So while you are bound to find popular articles out there crowing about the fact that there is a “central gene” connected to autism, don’t be mistaken: it’s still a complex situation.

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RNA Methylation

People rarely understand just how complex molecular biology really is. People are out there looking for the “autism gene” or “genes,” but have only found a low percentage of people who can be connected to a specific genetic change in a particular protein-producing gene. For many people, that means that environment is likely to be the main cause. However, there are many other factors in molecular biology that will have an effect on cellular outcomes that won’t be connected to a mutation in a protein-producing gene.

There are a variety of other things active inside a cell that affect protein expression and function. DNA can be methylated such that certain genes are turned off. RNA can be methylated as well, which affects translation of mRNA into proteins. The benefits of methylating RNA over DNA is that the cell is able to respond to its environment much more quickly. As the linked article notes, this allows for proteins to be turned on at synapses very far from the neuron’s nucleus. Both forms of methylation are of course a result of a protein or protein complex, meaning there is a gene or set of genes involved in them as well. So it still ends up being genetic–the only thing is that we won’t be looking for direct proteins, but rather proteins involved in these regulatory processes.

Insofar as the numbers of certain proteins in synapses is connected to certain varieties of autism, one should definitely look at regulatory elements in the production of those proteins, the transport of those proteins, the folding of those proteins, and the insertion of those proteins into the membrane when relevant. Those will all involve completely different protein complexes and processes, meaning there are a large number of potential pathways to the same basic outcome.

I think it’s important to learn how the various forms of neurodiversity come about simply because I support any and all basic research. I do think, though, that we need to change people’s attitudes about autism in general as we make these discoveries. It may be–and it’s likely to be–the case that those with such severe autism that they are rendered severely disabled (autism 3) are genetically quite different from the rest (autism 1 and 2), and that there might be a very wide variety of things we’re placing under the “autism” umbrella.

At the same time, it’s clear that my autism 2 son inherited his autism from me, though I’m only autism 1. This suggests either an environmental factor also being in play, or combinations of genes , or both affecting degree. There may be gene combinations which result in autism, so that if for example, you have gene X and gene Y, and mutation x’ and mutation y’, then XY would be neurotypical, X’Y would be neurotypical, XY’ would be neurotypical, and X’Y’ would be autistic, for example. Or there could be certain benefits to X’Y or XY’ for those individuals, yet when they get together and make an X’Y’ autistic child. Or X’Y’ is more sensitive to environmental factors than are the other three combinations, such that in the right environment, even X’Y’ won’t result in autism.

As I said, these things are very complex. Anyone who tells you they have a simple answer to the cause of autism is selling snake oil.