Thursday, 23 February 2012

Flame-proofed genetically-engineered mice and autism

If you clicked on to this post expecting to see the very latest in 'superhero' mice complete with special flame-resistant powers, I'm afraid that you are going to be disappointed. If however you are interested in how genes and environment wrapped up in 'the new kid on the block discipline' of epigenetics might provide some clues about autism-like behaviours, you might just be in luck.

Not quite Mickey @Paul Whiteley
The study in question is this one by Woods and colleagues* with some interesting observations on what happens to a genetically-engineered mouse exposed to polybrominated diphenyl ethers (PBDEs). PBDEs have been covered on this blog previously with regards to autism. The net result of the work so far suggested that just about everyone is carrying some level of these POPs in them but perhaps some responses to these chemicals might be slightly altered in cases of autism for whatever reason (see here).

The latest study from Woods et al went one stage further:

  • Mice were genetically-engineered to carry a defect in the methyl-CpG-binding protein 2 gene MECP2 (Mecp2-308) similar to that seen in Rett syndrome (RTT).
  • These female mice were exposed perinatally to BDE-47, mated with male wild-type mice and their offspring examined for various developmental, behavioural and epigenetic outcomes.
  • The main results: Mecp2-308 females exposed to BDE-47 were less fertile. Their female offspring also engaged in less social interaction with familiar mice alongside some issues with learning and memory coinciding with global hypomethylation of adult brain DNA (changes to DNA methyltransferase 3a, Dnmt3a). 
  • In short: epigenetic pathways were implicated in social and cognitive outcomes.

There are a few important points to note from this research. Primary among them is the issue of whether Rett syndrome, or more specifically the mutation associated with Rett syndrome, is the same as autism in a wider context. Looking at the current ICD and DSM listings, Rett syndrome (RTT) is a condition with a few ties to autism (at least for now).

First reported by Dr Andreas Rett, an Austrian physician, RTT is now known to be a genetic condition which almost exclusively affects girls (almost exclusive). Although still the source of some investigation, diagnosis of RTT is predominantly carried out on the basis of observed features and characteristics complemented by genetic testing for mutations on the X chromosome gene MECP2 and other less common mutations. The observed behaviours associated with RTT overlap with autism and also other conditions such as cerebral palsy. At least one of the authors on the Woods paper, Prof. Janine LaSalle, has a bit of an interest in the epigenetic links between RTT and autism.

Translating results from a mouse model to real-life autism has been covered on this blog in previous posts so I'm not going to get too deeply into that argument. Suffice to say that rodent models are still finding some favour as models of autism**. I suppose the fact that female offspring of dams with mutation & exposure were the ones where most of the interesting results were found at least provides some support for the whole nature-nurture relationship observed and the focus on the X-chromosome (females = XX, males = XY).

This is an important study and certainly sets a precedent for looking at the effects of environmental factors on other genetic findings related to autism via the engineered mouse model approach. Having said that I am trying not to get too excited about such findings given the lack of consistent genetic markers for autism, the wide heterogeneity and numerous comorbidities present and the number of potential environmental factors potentially at work.

To finish, a song from Sheffield's rock-tastic royalty called animal.

* Woods R. et al. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Human Molecular Genetics. February 2012.
DOI: 10.1093/hmg/dds046

** Buxbaum J. et al. Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features. Molecular Autism. Feburary 2012.
DOI: 10.1186/2040-2392-3-1