Angelman Syndrome Alliance Research update

ASI as part of our ongoing funding of  research are delighted to be able to provide a summary of the projects to date. Kindly complied by Annette Kent, they are explained in a family friendly version with a glossary to assist. Please see our research page on this website for the full summary.


Angelman European Alliance

We were delighted to be represented at the 2016 International Scientific Conference by Sarah Roarty and Annette Kent. The following is a summary of the two awardees, whom we are contributing funding to. It also explains the 2016 awardees. A glossary of terms at the end is also included to help as background. This was a really well attended meeting of parents, scientists and country organizations from many parts of the world, making it a truly international meeting.


Stormy Chamberlain, Assistant Professor of Genetics and Genome Sciences, University of Connecticut Health Centre, kicked off what was a day of high level science. Stormy spoke about her work with pluripotent stem cells and the steps they are taking to generate and identify an Angelman Syndrome (AS) neurons generated from these stem cells. Once generated these AS neurons will facilitate greater understanding of events in AS.

Ben Philpot, Department of Cell Biology and Physiology, University of North Carolina, later in the day gave a very clear concise summary of his focus on the white matter deficits in AS and the meaning of the same. He also spoke about the hyper-excitability within AS and the loss of UBE3A from inhibitory neurons increasing the susceptibility to seizures.

Chloe Simmons from FAST Australia, presented on the Global Registry that has been established by FAAT Australia for AS. This registry aims to capture information about individual AS patients to provide a collection of data to assist with future research.

Other presentations included details on the key features of AS mouse model, genetic approaches to reinstatement of the UBE3A, and novel therapeutic approaches. There were presentations also from the awardees from previous ASA funds and more recent awardees. Summaries of this work is given below:

Previous awardees
1. Dr. Ben Distal, AMC Amsterdam
Target identification for E6AP

The purpose of this project was to identify the target for E6AP, the protein produced from the UBE3A gene. This work also focused on the breakdown pathway involving proteasomes and the ubiquitination process, a process by which very small molecules are tagged with ubiquitin molecules and degraded by proteasomes.

Experiments which included proteasome quantification and in-vitro system bacterial ubiquitination, confirmed the presence of 4 interactors. In particular, there was the RPN10 molecules that binds to E6AP, the AZUL domain. Identifying the target of E6AP enables understanding of how the protein molecules work and what action could be taken.

2. Dr. Geeske van Woerden – Prof. Dr. Ype Elgersma
In vivo characterization of proteins that interact with UBE3A.

This work relates to the characterization of proteins, PML and RPN10 which are overexpressed in in-vitro systems when UBE3A is deficient. In-vitro experiments on cells have studied the alterations in neuron shape. In-vivo experiments using in-utero mice have used the electroporation (a process of introducing DNA or chromosomes into bacteria or other cells using an electrical pulse to open the pores in the cell membranes briefly) method and observed changes in the neuronal migration and UBE3A silencing observed a neuronal migration deficit in the developing mice.

PML – higher expression of the PML gene was observed in the mutant mice (PML gene encodes a protein which is a tumor suppressor, promyelocytic leukemia). PML has been shown to play an important role in the development of the neocortex. In-vitro experiments show that the overexpression of PML impairs the maturation of neurons, the in-vivo equivalent has shown that the increased levels of PML results in profound defects of migration, in that reducing the levels of this protein shows an improvement on cognitive and motor tests in animal model of AS.

RPN10 – It shows that RPN10 is a substrate for almost all E3 ligases, it is not degraded by UBE3A. Reduction in RPN10 can result in a migration delay, while the overexpression has no effect. Since it is an important protein for brain development, work is still ongoing to figure out what its function in AS.
2016 awardees

1. Dr. ssa Silvia Russo – Dr. ssa Tizana Borsella
Characterisation of synapses of neurons in AS

Recent studies have shown that cognitive deficits in AS are partly due to defects in the synapses of neurons of patients. In these special structures, called synapses, they are irregular shape, there are fewer of them and they work differently. Synapses are critical for learning memory and cognitive function, as they represent the point of contact between neurons and are necessary for the passage of information within neurons of our brain.

They will study the mechanisms that causes the changes in synapses in AS in an animal model (mice) and a human model. The Russian partners will generate human models using stem cells from patients’ blood and then developed into neurons. This project will focus on a specific group of proteins, JNKs proteins, which play an important role in regulating neuronal function.

The therapeutic action of D-JNK11, a specific inhibitor of JNK was presented in a model of Alzheimer’s disease. It is important to stress that the molecule has already passed phase II clinical trials for the treatment of neurodegenerative diseases and phase III for care of hearing loss. To summarize the objective of this proposal is to investigate the involvement of JNK protein in AS and investigator the potential therapeutic effect of D-JNK11.

2. Dr. Ben Philpot
Quantifying EEG abnormalities and identify biomarkers in AS

Epilepsy is very common in patients with AS (90%) and the underlying neural alterations can be measured non-invasively through the EEG. The EEG of AS patients has a distinctive profile that allows a qualitative assessment, but not a quantitative measure that can be evaluated strictly by analytical methods.

There is the unmet need to quantify the EEG profiles in individuals with AS to deepen the understanding of the basic circuits involved in these abnormalities through studies in the mouse AS model. The hypothesis is that a study that parallels EEG in humans and mice with AS, using new clinical biomarkers will make quantitative methods possible, and at the same time be useful for understanding for the mechanisms. In collaboration with two clinics dedicated to AS in the United States, their goal is to improve clinic trials by identifying objective and impartial biomarkers.

Pluripotent stem cell are master cells. They can potentially produce any cell or tissue the body needs to repair itself. This “master” property is called pluripotency.
White matter is one kind of brain tissue. There are 2 kinds of tissue in the central nervous system (brain and spinal cord) i.e. grey matter and white matter. Grey matter has a pinkish-grey color in the living brain, contains the cell bodies, dendrites and axon terminals of neurons, so it is where all synapses are. White matter connects different parts of grey matter to each other.
Hyper-excitability is an excessive response to a stumuli, in particular those nerve stimuli.
Proteasomes and the ubiquitination process is the main way that proteins are broken down in human cells. A breakdown in this process results in the accumulation of proteins and can be the basis of many diseases.
AZUL domain is a specific location on UB3EA gene.
PML is promyelocytic leukemia protein. This protein is involved in many cellular processes including cell cycle progression, DNA damage repair and others.
In-vivo experiments are experiments done within the living body of an animal or human.
Electroporation is the process of getting DNA or chromosomes into bacteria or other cells using a pulse of electricity to open the pores in the cell membranes/surface briefly.
Neuronal migration is the method by which neurons travel from they are created to their final position in the brain as the brain develops.
Neocortex is a part of the cerebral cortex concerned with sight and hearing in mammals, regarded as the most recently evolved part of the cortex.
Synapses is a structure that allows a nerve cell to pass an electrical or chemical signal to another nerve.

Angelman Syndrome Alliance call to research January 2016.


Call for Applications for Research Grants on  Angelman Syndrome

Call will be open between the 25th November 2015 and the 24th of January 2016

The Angelman Syndrome Alliance (ASA) supports research on Angelman syndrome with up to 300 000 Euros to be awarded at the next International Angelman Syndrome Scientific Conference. The Angelman Syndrome Alliance is (currently) an initiative of the following parent organisations: AVO (Austria), ASB (Belgium), ASFA (France), Angelman e.V. (Germany), AIA (Ireland), Israeli Angelman Syndrome Foundation (Israel), ORSA (Italy), PWAV (Netherlands), Angel (Portugal), ASSERT (United Kingdom), and the Nina Foundation (consortium organization on AS science). Their mutual aim is to join forces and funds to increase the financial support of dedicated research projects and thereby intensify research on Angelman Syndrome.

Angelman Syndrome is a genetic disorder resulting from a loss of function of the UBE3A gene which encodes the ubiquitin E3 ligase E6AP. Angelman Syndrome is characterised by severe intellectual disability, lack of speech, motor coordination deficits, sleep disturbance, and usually a happy demeanour.

Researchers of any country are invited to apply for research grants covering preclinical (basic) research as well as translational research such as mechanism-based controlled trials. Applications for behavioural therapies are not eligible at this point.
Proposals addressing new ideas/concepts about the pathogenesis of Angelman Syndrome are particularly invited.
The duration of the grant is flexible, but the maximum is 4 years. There will be an evaluation by the SAB of the project after completion of 50% of the total time and at the end. Every 6 month interim reports are to be sent to Faustine Bourgoin in simple language (lay version) with supporting pictures to inform the parent organisations in more general terms about the project progress.

The application procedure is two-step:
1. First, a short application has to be submitted on the ASA website : CLICK HERE (Deadline 24th of January 2016);
2. A maximum of 10 applicants will be selected for step 2 will be informed by end of February 2016. Selected applicants will then be invited to submit a detailed application by 3rd of May 2016.
3. 1 – 2 applicants will be awarded a grant at the bi-annual meeting of the Angelman Syndrome Alliance on the 30th of September 2016 in Portugal.
4. Via uploading their documents, the applicants accept the terms and conditions of the ASA contract (available on the website). The awardees will be expected to give the ASA-AWARD LECTURE at the beginning and the end of the project.

The short application (step 1) should include the following:
1. Cover letter including the title of the proposal and the name of the principal investigator
2. Two-page summary of the proposed research including paragraphs on the hypothesis, background, research plan, principal methodology, and the significance of the proposed research. An overview of the budget must also be included (indirect costs cannot be applied for).
3. Curriculum vitae of the applicant

All applications should be written in English language using Times New Roman, 10 point, 1.5 spaced.
Proposals involving laboratory animal testing must be approved by the respective institutional review boards before funding can be released.
All proposals, including cover letters, should be uploaded at the ASA website:

à Questions about the grant application procedure and about the contract should be directed to the NINA Foundation at:
à Questions about research on Angelman Syndrome should be directed to:
à All general questions should be directed to:

Betty Willemsen and Martijn van Steensel are part of the scientific AS organization named ‘Nina Foundation’ (NF) which is organising the call on behalf of the Angelman Syndrome Alliance (ASA). Harald Sitte (MedUni Vienna) is the chairman of the ASA Scientific Advisory Board (SAB); further members are Lidia Larizza (Univ. Milan) and Martin Scheffner (Univ. Konstanz). Faustine Bourgoin is part of AFSA, the French AS parent organization, and supports ASA and SAB with communication and tender process matters.

Glossery of scientific terms – new for 2016

Having recently sat in on a number of scientific presentations we thought it might be useful to include a new post on explaining terms. This is something we will update on a regular basis and thank Annette Kent for preparing them. Annette has come on board to support us in the area of science and research.

A target is an entity e.g. protein, gene, structure in the body that can be altered negatively or positively for the treatment of a condition/illness. The change in the target may correct the error or alleviate the problem associated with the condition/illness. Novel targets are those are being researched and have the potential to be used in future treatments.

Rescue drugs are those that used when a condition occasionally gets worse i.e. becomes acute. These medicines are not taken routinely or every day.

Orphan drugs are drugs that deemed suitable for treating very rare diseases also called orphan diseases. Orphan diseases are those that affect a small percentage of the population. These rare disease are usually genetic and present for the person’s entire life.

Proteins are very important compounds in the body and are responsible for doing a lot of the work in the cells of the body including regulating the cells activities, providing structure and functions within cells and organs of the body.




RTE radio 1 documentary An Angelman Year.

June 20th RTE Radio 1  – An Angelman Year.


Parent Conference Dublin July 20th Video sessions.


Angelman Syndrome Ireland Parent workshop  July 2013 video sessions  are available to view via Youtube on our home page.

Speakers sesssions:

  • Heather Lynch Director of Camphill Communities in Ireland.
  • Prof Ben Philpot, from the University of North Carolina US
  • Heather J E Crawford MBE, AHP Manager for Children’s Services/ Lead Professional for Speech & Language Therapy South Eastern Trust. NI