Families & Caregivers
Genetics 101
Understanding the Genetics of Angelman Syndrome
Welcome to Angelman Syndrome Genetics 101. This section reviews essential genetics concepts to help you better understand the causes of Angelman syndrome (AS). For a deeper dive, check out Genetics 201.
What are Chromosomes and Genes?
Our bodies are made up of tiny building blocks called cells. Inside almost every cell are structures called chromosomes— strands of DNA that act like instruction books telling our bodies how to grow, develop, and function. Most people have 46 chromosomes, arranged in 23 pairs: one copy of each chromosome inherited from the mother (maternal) and the other copy of each chromosome from the father (paternal).
Each chromosome contains hundreds to thousands of genes. A gene is a segment of DNA that provides the instruction to make a protein. Proteins do essentially everything in our body—controlling growth, development, and everyday functioning.
The UBE3A Gene and Chromosome 15
One important gene is called UBE3A, which is located on chromosome 15. This gene encodes the UBE3A protein, which plays a vital role in brain development and function and is important for tasks like learning, motor coordination, and communication.
Most people have two copies of chromosome 15 and therefore two copies of the UBE3A gene—one from each parent. The copy from the egg is called maternal, and the copy from the sperm is called paternal.
What Is Imprinting?
In most body tissues, both copies of the UBE3A gene are active, meaning that they are used to make UBE3A protein. However, in brain cells (specifically neurons), only the maternal copy of UBE3A is active. The paternal copy is turned off, because UBE3A is an imprinted gene. Imprinting is when a gene is expressed differently based on the parent of origin, or whether it came from the egg or from the sperm. “Neurotypical” people (with regard to AS) have the maternal UBE3A gene turned on, paternal UBE3A gene turned off in the brain.
If the maternal UBE3A copy is missing or not working properly, there is no backup, and the brain is left without functional UBE3A protein.
This lack of functional UBE3A protein in the brain is what causes the symptoms of Angelman syndrome.
What Is the Cause of Angelman Syndrome?
Angelman syndrome is caused by a lack of functional UBE3A protein in the brain. This can occur in several different ways, known as genotypes:
Deletion: The most common cause, where a section of the maternal chromosome 15 including UBE3A is missing.
UBE3A Mutation: The maternal UBE3A gene is present but has an error within the DNA, resulting in a less functional or non-functional UBE3A protein.
Uniparental Disomy (UPD): The individual inherits two copies of chromosome 15 from the father and none from the mother, so both copies of UBE3A are silenced in the brain.
Imprinting Center Defect (ICD): The maternal UBE3A gene is present but is silenced due to an error in the imprinting process
Mosaic: Less common, not all cells in the body are affected.
These different genotypes all result in a lack of UBE3A protein where it’s needed most: the brain.
Angelman Syndrome Inheritance
In most families, Angelman syndrome is not inherited. The genetic differences that lead to AS most often occur as random (sporadic) events during the formation of egg cells or early in embryonic development. However, in a percentage of families, AS can be inherited, most often in families with UBE3A mutations or ICD-deletion. Understanding the specific genotype is critical for determining chances for other family members and for testing family members.
Why the Absence of UBE3A Protein Matters
The UBE3A protein plays an essential role in brain function. It helps control how brain cells communicate. One of its many roles is to tag other proteins for removal or other cell processes, which is important for keeping our brain cells healthy and functioning properly. We do not yet understand all the functions of UBE3A, but we know that without UBE3A, brain cells do not communicate correctly, affecting learning, movement, and behavior. This leads to the characteristic symptoms of Angelman syndrome.
Summary
Angelman syndrome is caused by genetic differences on chromosome 15 affecting the UBE3A gene.
Due to imprinting, only the maternal copy of UBE3A is active in brain cells (neurons).
The absence of maternal UBE3A or errors within the maternal UBE3A gene result in no functional UBE3A protein being produced in the brain.
This loss of functional UBE3A causes the neurological symptoms seen in Angelman syndrome.
The likelihood of AS being inherited varies by genotype. In most families, it is not inherited, but the chance varies depending upon the genotype and the family testing. Genetic counseling can help you understand the chances in your family.
For Genetics 201, head over to this page.