Showing posts with label AUTS2. Show all posts
Showing posts with label AUTS2. Show all posts

Monday 5 May 2014

Autism, Schizophrenia, MR, 5 Overlapping Genes and Epigenetic Dysfunction

In a recent post I raised the issue of maybe we should be looking at the schizophrenia research, given that the condition appears very closely related to ASD.  Then I got rather side tracked by MR (Mental Retardation), now known as Intellectual Disability, in polite society.  Since schizophrenia is adult-onset, I thought it might attract some serious research; indeed it does.  

It turns out there may have been more sense than you thought, in my making “connections” between autism, schizophrenia and MR.

A striking study has just been published from Trinity College, Dublin.  It draws these three conditions together using genes and makes a remarkable conclusion regarding epigenetics.  Epigenetic change has already been highlighted as a key process behind the development of autism. 

The full paper is not openly available, but below is the abstract and here is a press release from the University

De novo mutations in schizophrenia implicate chromatin remodelling and support agenetic overlap with autism and intellectual disability

An excellent lay person’s summary is available in this article:-

A Single Genetic Variation Is Shared By People With Schizophrenia ,Autism, And Intellectual Disability


Scientists believe some cases of schizophrenia are caused by gene mutations passed from parents to children with environmental factors exacerbating the effects of such mutations. Yet researchers also believe some cases of the mental disorder may be caused by de novo genetic mutations (DNMs). DNMs are new defects in genes that occur only in offspring — in such cases, neither parent possesses the same defects as the child. These mutations are simple copying errors caused during mechanical DNA replication. They occur infrequently in every human being during sperm and egg development, but typically they have no overall impact on human health.

However, when de novo mutations occur in a gene or genes indispensable for normal development they have devastating consequences. For this reason, McCombie and his colleagues, in an ongoing collaboration with Dr. Aiden Corvin of Trinity College, Dublin, hypothesized there may some special link between schizophrenia and DNMs.

For the current study, then, the team enlisted the help of 42 “trio” families in which the child, but neither parent, was diagnosed with schizophrenia and/or psychosis. They also enrolled 15 trio families with a history of psychosis. Then they set to work, searching for de novo mutations. What did they discover?

Among the 42 affected children in the study, they discovered de novo mutations in three genes: AUTS2, CDH8, and MECP2. (In prior genetic studies, mutations on these very same genes have been identified in people with autism.) Two other mutated genes found in the participants — HUWE1 and TRAPPC9 — have been similarly linked to people with intellectual disability.  Of these five "overlapping" genes, three — CHD8, MECP2 and HUWE1 — play a role in what scientists call the epigenetic regulation of transcription. That is, these three genes are involved in a complex molecular process that determines when and which genes are switched on or switched off.

"There's a growing awareness of the importance of epigenetic regulation during brain development, as well as in cognition in the mature brain," said Dr. Shane McCarthy, a CSHL research investigator and lead author of the new study. This regulation is the reason why the team’s discovery is so important — normal brain development depends on these genes. With this study, then, de novo mutations of these genes have been linked to not just schizophrenia but autism and intellectual disability as well.


This is actually all very important.  Epigenetics is a mechanism whereby the environment can affect your genes (flipping a specific gene, from on to off, or off to on).  Epigenetic changes can be inherited and so pass through the generations.  In theory, it can potentially be reversed.  Epigenetic change is not a good thing; but it seems that in people with autism, key genes have mutated that make them more prone to such epigenetic change.  So this might explain why people with autism are prone to so many other things (comorbidities) as well.  It might also explain why they are autistic in the first place; they were already at risk, but in addition they were more vulnerable to any kind of environmental insult.  The number of environmental insults is increasing in modern society and we are slowly accumulating some of the epigenetic flaws of our ancestors.  This might explain the increase in autism, particularly in modern societies, where environmental insults are more likely.

The other interesting point is that the five overlapping genes related to autism, MR and schizophrenia in the study are all new mutations; they were not inherited from the parents.  Many parents, and indeed pseudo-experts with their therapy “protocols”, often suggest that autism is nothing to do with genetics and they look for other factors to "blame", like heavy metals.  Parents clearly do not want to feel autism was their “fault”.  As this study shows, these five critical genetic causes are not inherited, they are just the result of imperfections in the copying process.  So in the case of these five genes, parents can accept the scientific evidence without any feeling of guilt. 

People with autism, but no MR, should probably count themselves very lucky indeed.