Next Steps for Dup15q/Angelman Syndrome Research

Quick Overview

The discussion at the 2016 ASF-Dup15q Scientific Symposium focused on the appropriateness of animal models for Dup15q/Angelman Syndrome research. The potential role of HERC2 as a modifier of UBE3A was highlighted, suggesting a need to rethink the design of mouse models. The discussion also touched on the potential of using flies for easier modelling. The importance of considering subtle behavioural effects and the potential role of other genes in the deletion was also discussed. The conversation moved on to the potential of using ASOs versus chemical therapeutics, with the complexity of the antisense transcript and the need for human sequence being highlighted. The discussion concluded with the suggestion of more collaboration across model systems to whittle down potential compounds for study.


The HERC2 points raised by Martin highlight an issue that we may not consider often: are the animal models we use for Dup15q and Angelman Syndrome appropriate? Only a few animal models have been suitable in terms of the number of genes duplicated, such as in the Takumi mouse. If HERC2 is indeed functioning as a modifier of UBE3A, should we rethink some of the ways we design mouse models?

Animal Models and Their Limitations

In flies, it might be easier, but in mice, we should consider that we may not see some subtle behaviour effects if we don’t add HERC2 and UBE3A to both the deletion class and the duplication class. This is because the UPD cases and the point mutation cases of Angelman Syndrome have milder effects than the deletion class.

The Role of HERC2

Martin showed some strong evidence that HERC2 may be a significant player in that modification. However, HERC2 is maybe important, but there are many other genes that are duplicated in that region. There’s not enough data to suggest that adding too much UBE3A and HERC2 alone is really causative.

The Takumi Model

In the Takumi model, HERC2 is supposed to be duplicated. It’s syntenic, right? And they tried to make it all the genes that had synteny, so I’m assuming it is.

The Question of Genetic Background

One of the things to consider is our genetic background. We often disregard the genetic background in animal models, but people have a significant amount of genetic background. There’s variability. So that’s a bigger problem that we won’t answer in this room for sure, but it’s something just to keep in mind that it may be something.

Current Therapeutics and Future Directions

Our therapeutic approach now should start considering not just UBE3A up or down regulation, but also targeting other proteins such as NHE6 and HERC2. This broader thought process about where we’re targeting our therapeutics for the disorder is starting to grow.


We need to collaborate more across model systems because then we can eliminate a lot upfront. If we have 1,000 compounds, and we whittle it down to 500 in flies with good homologs, and we whittle it down to another 50 in mice, and then we’ve only got five good candidates for the primate models. That’s the right way to do it.

Talk details

  • Title: Next Steps for Dup15q/Angelman Syndrome Research
  • Author(s): Larry Reiter
  • Author(s)’ affiliation: University of Tennessee Health Science Center
  • Publication date: 2016-09-06
  • Collection: 2016 ASF-Dup15q Scientific Symposium