Foundation Funds Development of Cell Models to Advance Research

A newly funded research project seeks to create cellular models that can be used to study two of the less common types of genetic abnormalities that cause Angelman syndrome.

The project, funded by the Foundation for Angelman Syndrome Therapeutics (FAST), will investigate uniparental disomy (UPD) and imprinting errors of the UBE3A (ubiquitin protein ligase E3A) gene.

Angelman syndrome is caused by the absence or malfunction of the UBE3A gene, located on chromosome 15. Everyone inherits two copies of this gene — one from each biological parent. Normally, only the copy of UBE3A inherited from the biological mother is “turned on” in nerve cells, and the copy inherited from the biological father gets “turned off” through a process called imprinting.

The most common causes of Angelman are microdeletions — loss of the part of maternal chromosome 15 where the UBE3A gene resides — and mutations, where the sequence of the gene is altered.

In UPD, which causes 3%–5% of Angelman cases, a person inherits two copies of chromosome 15 from their biological father, and none from their biological mother, so there isn’t a maternal copy of the UBE3A gene available. Imprinting errors — also called imprinting center defects, or ICD — are when the imprinting process that normally “turns off” the paternal gene erroneously turns off the maternal gene.

One strategy for treating Angelman syndrome that researchers are currently exploring is using therapies to “turn on” the paternal UBE3A gene that is normally “turned off” via imprinting. In people with microdeletions or mutations in the maternal gene, this strategy would theoretically cause cells to have one functional UBE3A gene that is “turned on” — which is what normally happens.

However, in people with UPD or imprinting deficits — because there are two functional UBE3A genes that are both turned off — there is a theoretical possibility that this kind of treatment could lead to activation of both UBE3A genes. It isn’t clear whether this abnormally high UBE3A activation would cause problems, largely due to a lack of research.

One of the obstacles in doing that kind of research is the need for appropriate models that scientists can use to study them. That’s where the new project comes in.

In the project, led by Albert Keung, PhD, of North Carolina State University, researchers will engineer human stem cell lines to create cells that mimic the genetic abnormalities seen in Angelman patients with UPD or imprinting defects. The model may also be useful for studying mosaicism — when a person has multiple genetically different sets of cells in their body.

In addition to studying the UBE3A gene, the new cell models may also be useful for studying other genes that are located nearby on chromosome 15. Many of these genes encode so-called noncoding RNAs, meaning RNA molecules that, unlike messenger RNA (mRNA), do not get used as a template to make proteins. Instead, noncoding RNAs help to regulate a variety of cellular functions.

The exact functions of the noncoding RNAs that are near UBE3A, and their implications in Angelman syndrome, aren’t well-understood. Because the new model will allow researchers to turn these genes “on or off” with relative ease, it may be useful for studying these noncoding RNAs.

According to a FAST press release, the project “aims to provide the Angelman syndrome research community a set of cell lines that can be used to efficiently model the biology of ICD and UPD … This work will create valuable resources which will be shared with the AS [Angelman syndrome] research community and will help to drive AS research forward with the ultimate goal of accelerating drug development in Angelman syndrome for each and every genotype.”