Genes of Interest

Genes of Interest in chromosome 15q duplication syndrome

Chromosomes carry genes that control the physical development and behavior of every individual. To understand the developmental problems caused by chromosome 15q duplication syndrome, it is helpful to be aware of some of the genes of interest on this chromosome.

What do we know about the genes involved in duplications of 15q11.2-q13.1?

The most commonly duplicated region is gene rich, including genes that are expressed from both paternal and maternal chromosomes as well as genes that are expressed differently based on the parent of origin of the chromosome.

Because maternally derived 15q duplications are most often associated with developmental problems, including autism, cognitive impairments, and seizures, there is a lot of scientific interest in the two known maternally expressed genes UBE3A and ATP10A (aka ATP10C). It is likely that other genes within the duplication and beyond are contributing to the symptoms of chromosome 15q11.2-13.1 duplication syndrome.

The UBE3A gene is present in 4 copies in most individuals with idic(15) and 3 copies in most individuals with interstitial duplications. Studies have shown that the extra copies of the gene are active in individuals with idic(15) chromosomes. The UBE3A gene provides instructions for making an enzyme called ubiquitin protein ligase E3A. This enzyme is involved in targeting other proteins to be broken down (degraded) within cells. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells. Both copies of the UBE3A gene are active in most of the body's tissues. In the brain, however, only the copy inherited from a person's mother (the maternal copy) is normally active.

The ATP10A (also referred to as ATP10C) gene is currently being studied to determine if it plays a role in the development of the autism spectrum disorders associated with maternal rearrangements of chromosome 15. The exact function of this gene is not known, but it is believed to produce a protein that helps transmit molecules called ions (such as calcium) between cells in the body. In addition to its location on chromosome 15 and imprint status, the assumed function would involve it in maintenance of cell membrane integrity, and it may therefore be critical for cell signaling in the central nervous system.

There are also 3 GABAA receptor genes in the region that is commonly duplicated. These three GABA receptor subunit genes are called GABRB3, GABRA5 and GABRG3. GABA (g-aminobutyric acid) is a neurotransmitter (a chemical that carries messages between nerve cells). When GABA communicates to nerve cells, it causes them not to respond to other stimulatory signals in the brain. Thus, GABA is largely considered an inhibitory neurotransmitter, although its activity actually evolves with age.  After infancy, the overall effect of GABA and GABAA receptors is to stabilize the activity of nerve cells.

It has been proposed that impaired GABA function, especially GABAA receptor function, may play an important role in autism and Angelman syndrome. It is hypothesized that the role of GABA receptor subunit genes in autism most likely comes via complex gene-gene interactions. GABA also plays an important role in seizures. Because GABA inhibits neurons from firing, and seizures are caused by inappropriate or unregulated firing of nerve cells, increasing GABA activity through its receptors can cause the system to stabilize, and decrease seizures.

The 3 GABAA receptor genes contain instructions for making proteins that form GABA receptors. A functional GABA receptor comprises several parts, and it is believed that expressing extra copies of some components will actually lead to fewer functional receptors.