What Are the Different Genetic Variants of Angelman Syndrome?
Genetics of Angelman syndrome
We all have two copies of the UBE3A gene. We inherit one of these copies from our mother and one from our father. In some regions of the brain, we only use the copy we inherit from our mother. In these areas, the paternal copy of UBE3A is silent.
The UBE3A gene encodes for a protein that helps mark proteins for recycling after they fulfill their role in the cell. If there is a mutation (a small change in the DNA) in this gene or it cannot function properly for some reason, the protein it encodes for doesn’t work as intended. As a result, other proteins stay active for longer than they should, causing Angelman syndrome.
There are different variants of Angelman syndrome based on the genetic events that cause it.
Lack of maternal UBE3A
The lack of part of the maternal chromosome 15, which contains the UBE3A gene, causes 70% of all Angelman syndrome cases. Without this copy, certain brain regions cannot make UBE3A protein, even if the paternal copy of the gene is healthy.
UBE3A gene mutations
About 11% of Angelman patients have mutations in the UBE3A gene. These mutations may change whether cells make protein from the gene, or cause cells to make the protein with mistakes that prevent it from working normally.
Imprinting center defects (ICD)
In about 5% of Angelman syndrome patients, changes in the maternal copy of the UBE3A gene cause the maternal copy to be “silenced,” as if it were the paternal copy. This is an imprinting defect.
In very rare cases, patients have a normal maternal copy of the UBE3A gene in some brain cells, while other cells have a defect that prevents a normal protein from being made. Patients with this mosaic variant tend to have milder symptoms, because the disease does not affect all relevant cells.
Uni-parental disomy (UPD)
In rare cases again (about 1%), some with Angelman syndrome inherit two copies of the paternal UBE3A gene. Since the paternal copy of the gene is inactive in certain regions of the brain, these regions have no UBE3A protein, even with two genetically normal copies of the gene.
For about 10% of all people with Angelman syndrome-like symptoms, the cause of their disease is not clear. These individuals may not have Angelman at all, but another disorder. Alternatively, they may have a new, previously unidentified variant of Angelman syndrome.
Last updated: April 25, 2020
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