Foundation funds development of Angelman cell models for research
A recently funded research project aims to create cell 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 Angelman Syndrome Therapeutics Foundation (FAST), will investigate single-parent disomy (UPD) and printing errors of the UBE3A (ubiquitin protein ligase E3A gene).
Angelman syndrome is caused by the absence or dysfunction of the UBE3A gene, located on chromosome 15. Each 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 is “turned off” by a process called imprinting.
The most common causes of Angelman are microdeletions – loss of the part of the maternal chromosome 15 where the UBE3A the gene resides – and mutations, where the gene sequence is altered.
In UPD, which causes 3% to 5% of Angelman’s cases, a person inherits two copies of chromosome 15 from their biological father and none from their biological mother, so there is no maternal copy of UBE3A gene available. Printing errors – also known as print center defects, or ICDs – occur when the printing process that normally “turns off” the paternal gene mistakenly turns off the maternal gene.
One treatment strategy for Angelman syndrome that researchers are currently exploring is to use therapies to “turn on” the father. UBE3A gene that is normally “turned off” via printing. In people with microdeletions or mutations in the maternal gene, this strategy would theoretically cause the cells to have a function UBE3A gene that is “turned on” – which normally happens.
However, in people with UPD or printing deficits – because there are two UBE3A genes which are both turned off – there is a theoretical possibility that this type of treatment could lead to the activation of both UBE3A the genes. It is not clear whether this abnormally high level UBE3A activation would pose problems, largely due to a lack of research.
One of the barriers to this kind of research is the need for appropriate models that scientists can use to study them. This is where the new project comes in.
As part of the project, led by Albert Keung, PhD, of North Carolina State University, researchers will design human stem cell lines to create cells that mimic genetic abnormalities seen in Angelman’s patients with UPD or defects. printing. The model can also be useful for studying mosaicism – when a person has several 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 located nearby on chromosome 15. Many of these genes encode so-called non-coding RNAs, i.e. RNA molecules which, unlike messenger RNA (mRNA), are not used as a template to make proteins. Instead, non-coding RNAs help regulate a variety of cellular functions.
The exact functions of non-coding RNAs that are close UBE3A, and their implications for Angelman syndrome, are not well understood. Since the new model will allow researchers to turn these genes on or off with relative ease, it may be useful for studying these non-coding RNAs.
According to a FAST Press release, the project “aims to provide the Angelman syndrome research community with a set of cell lines that can be used to effectively model the biology of ICD and UPD … This work will create valuable resources that will be shared with the ace [Angelman syndrome] and help advance AS research with the ultimate goal of accelerating the development of Angelman syndrome drugs for each genotype. “