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.