The UBE3A gene codes for a protein important in the brain. It is a ubiquitin-protein ligase E3A, which helps regulate the stability of various proteins. UBE3A influences processes within the nervous system, impacting brain development and function.
The Role of UBE3A
UBE3A’s normal function involves a process called protein ubiquitination. This involves tagging specific proteins with a small protein called ubiquitin, which signals cellular structures called proteasomes to break down or modify these proteins. This system maintains cellular health and balances protein creation and degradation, particularly at synapses, the communication points between nerve cells.
In the brain, UBE3A is important for neuronal development and synaptic plasticity—the ability of synapses to strengthen or weaken over time. UBE3A regulates the development of excitatory synapses by controlling the degradation of the synaptic protein Arc. When UBE3A is functioning properly, it helps prune unnecessary synapses during childhood and adolescence, a process that allows essential synapses to grow stronger and more stable, contributing to learning and memory.
UBE3A and Angelman Syndrome
Abnormalities in the UBE3A gene lead to Angelman Syndrome. This neurodevelopmental disorder arises when the maternal copy of the UBE3A gene is missing or not functioning. The most common cause, accounting for about 70% of cases, is a deletion of a 5- to 7-megabase segment in the maternal chromosome 15q11.2-q13 region, which contains the UBE3A gene.
Other causes include mutations within the maternal UBE3A gene (about 11% of cases), which prevent the gene’s expression or alter its function. About 6% of cases involve imprinting center defects. Genomic imprinting is a phenomenon where only one copy of a gene, either from the mother or father, is active. In certain brain regions, the paternal copy of UBE3A is silenced, meaning the brain relies solely on the maternal copy for UBE3A protein. If the maternal copy is compromised through deletion, mutation, or an imprinting defect, it results in a lack of functional UBE3A in neurons, leading to Angelman Syndrome.
Understanding Angelman Syndrome
Angelman Syndrome manifests due to the dysfunction of the UBE3A gene. Developmental delays are noticed around six months of age, with distinct features becoming apparent after one year. Individuals experience severe intellectual disability, profound speech impairment ranging from very few words to being nonverbal, and difficulties with walking and balance, often presenting with ataxia or a wide-based gait.
A distinctive behavioral pattern includes a happy demeanor, characterized by frequent smiling, laughter, and excitability, often accompanied by hand-flapping movements. Other common symptoms include seizures, which can begin in early childhood and continue into adulthood, and sleep disturbances. Some individuals may also exhibit feeding difficulties in infancy, low muscle tone, scoliosis, gastrointestinal issues such as constipation, and unique facial features like a wide mouth, widely spaced teeth, or a short, broad skull. Diagnosis involves genetic testing to identify UBE3A mutations or deletions.
Research and Emerging Therapies
Current research efforts are focused on understanding the UBE3A gene and developing therapies for Angelman Syndrome. Promising areas include gene therapy, which aims to introduce a functional copy of the UBE3A gene into affected cells. Another area involves antisense oligonucleotides (ASOs), which are designed to reactivate the paternal UBE3A allele.
The paternal UBE3A allele is silenced in neurons by a long non-coding RNA called UBE3A-ATS. ASOs can bind to this UBE3A-ATS, preventing it from silencing the paternal gene and thereby allowing the production of functional UBE3A protein. Clinical trials for ASO therapies are currently underway, showing potential for improving symptoms. Beyond ASOs, other pharmacological approaches and engineered DNA-binding proteins like zinc finger-based artificial transcription factors are being explored, offering hope for future treatments that could improve the quality of life for individuals with Angelman Syndrome.