UBE3A

Tissue distribution

Both copies of the UBE3A gene are active in most of the body's tissues. In most neurons, however, only the copy inherited from a person's mother (the maternal copy) is normally active; this is known as paternal imprinting. Recent evidence shows that at least some glial cells and neurons may exhibit biallelic expression of UBE3A. Further work is thus needed to delineate a complete map of UBE3A imprinting in humans and model organisms such as mice.

Function

The UBE3A gene encodes ubiquitin protein ligase E3A (also known as E6AP), a multifunctional enzyme that plays a crucial role in cellular protein homeostasis and neural development. Its primary function is to act as an E3 ubiquitin ligase, attaching ubiquitin molecules to specific substrate proteins, thereby marking them for degradation by the proteasome system. This process is essential for removing damaged or unnecessary proteins, maintaining cellular health, and regulating the balance of protein synthesis and degradation (proteostasis) at synapses, which is vital for synaptic plasticity, learning, and memory. In addition to its ligase activity, UBE3A also serves as a transcriptional co-activator, influencing the expression of genes involved in hormone signaling and neural function. Notably, in neurons, only the maternal copy of the UBE3A gene is typically active due to genomic imprinting, and disruptions in its expression are linked to neurodevelopmental disorders such as Angelman syndrome and autism spectrum disorders. UBE3A's precise regulation is therefore critical for normal brain development and function, as both loss and overexpression can lead to significant neurological and behavioral abnormalities.

Clinical significance

Mutations within the UBE3A gene are responsible for some cases of Angelman syndrome and Prader–Willi syndrome. Most of these mutations result in an abnormally short, nonfunctional version of ubiquitin protein ligase E3A. Because the copy of the gene inherited from a person's father (the paternal copy) is normally inactive in the brain, a mutation in the remaining maternal copy prevents any of the enzyme from being produced in the brain. This loss of enzyme function likely causes the characteristic features of these two conditions.

The UBE3A gene lies within the human chromosomal region 15q11-13. Other abnormalities in this region of chromosome 15 can also cause Dup15q and Isodicentric 15. These chromosomal changes include deletions, rearrangements (translocations) of genetic material, and other abnormalities. Like mutations within the gene, these chromosomal changes prevent any functional ubiquitin protein ligase E3A from being produced in the brain.

UBE3A associates with the E6 protein of certain strains of HPV. This interaction promotes the polyubiquitination and subsequent degradation of the tumor suppressor gene p53, thereby enabling the immortalization of infected cells. Strains of HPV with this ability have a higher risk of causing HPV-associated cancers. UBE3A is also known as E6AP or E6-associated protein in reference to this mechanism.

Interactions

UBE3A has been shown to interact with:

• BLK,
• Lck,
• MCM7,
• MECP2,
• Progesterone receptor,
• TSC2,
• UBE2D1,
• UBE2D2,
• UBE2L3,
• UBQLN1, and
• UBQLN2.