What genetic change causes Angelman syndrome?
Angelman syndrome is caused by the lack of a protein called E6AP, that is made by a gene called ubiquitin-protein ligase E3A (UBE3A). The UBE3A gene is part of a group of genes that are imprinted. Typically, our bodies use both the maternally-inherited and paternally-inherited copy of our genes to make whatever that particular gene's product is, like an enzyme or a protein. With imprinted genes however, one copy of the gene is switched on, and the other copy is switched off, based on which parent the gene was inherited from. With UBE3A, the maternally-inherited copy is "switched on", and makes UBE3A protein, while the paternally-inherited copy is "switched off" (imprinted) and does not make UBE3A protein.
There are four recognized types of genetic changes that can cause Angelman syndrome:
- Approximately 70% of individuals with Angelman syndrome have a deletion of the maternally-inherited copy of the UBE3A gene. Deletion that causes Angelman syndrome are usually de novo, meaning that the deletion occurred as a random event as the gene was being passed from the parent to the child.
- Approximately 11% of individuals with Angelman syndrome have a mutation in UBE3A. A mutation means that there is a change in the genetic information within a gene that causes the gene to work incorrectly or not at all.
- Approximately 7% of individuals with Angelman syndrome have inherited two copies of the chromosome on which UBE3A is located (chromosome 15) from the father and no copies of the chromosome from the mother. This phenomenon is called paternal uniparental disomy, meaning two copies of a chromosome (disomy) from one parent (uniparental). It is sometimes abbreviated as UPD.
- Approximately 3% of individuals with Angelman syndrome have a deletion of the Angleman Syndrome imprinting center, which controls the switching on and off of the UBE3A gene. Deletion of the imprinting center leads to an inability to switch on the maternally-inherited copy of UBE3A, which results in no UBE3A protein being made. Imprinting center defects are sometimes referred to as simply "imprinting defects" (IDs).
- Approximately ~10% of individuals who have a clinical diagnosis of Angelman syndrome (a diagnosis based on their physical features) do not have an identifiable genetic abnormality. This remains an area of ongoing study.
More Causes Content
What happens because of this change or mutation in Angelman syndrome?
A small protein called ubiquitin is known to play a role in neurologic development and neurologic disorders. In Angelman syndrome, a protein that interacts with ubiquitin, called ubiquitin ligase E3A (E6AP) is not produced. Normally, E6AP attaches ubiquitin to proteins that the body needs to break down, like a signal. This process is particularly important in the brain. When E6AP is not present or is not functional, this process does not work the way it is should, and proteins that would normally be broken down by the body are not.
It is not known exactly how this disruption to the protein breakdown process causes Angelman syndrome, although this is a topic of active research.
Does anything, like environmental factors, make Angelman syndrome worse?
Unlike conditions such as autism, which are thought to be the result of a combination of genetic and environmental factors, Angelman syndrome is a genetic disorder that is caused by the loss of function of a gene called UBE3A. Although the type of genetic change that causes UBE3A to not work have been correlated with mild differences in severity, there is no indication that environment plays a role in the severity of the major features of Angelman syndrome.
Some of the other medical conditions that are seen in individuals with Angelman syndrome, such as hyperactivity, hyperlocomotion, seizures, and sleep disorders may benefit from changes to the person's physical and social environment to ensure maximum developmental ability, safety, and well-being. For suggestions on various types of therapies that have been used for individuals with Angelman syndrome, refer to the Therapy Services page of The Angelman Network.[/link]