New UBE3A Missense Mutation Linked to Angelman Syndrome


Missense mutations cause Angelman syndrome in around 5% of diagnoses. However, researchers have often been unclear or unsure of the biochemical consequences of these missense mutations on the affected protein. According to Angelman Syndrome News, researchers were able to explore this through the discovery of a new UBE3A missense mutation in a young child in Australia.

The research, published in ACS Omega, centered around a young child in Australia. Within the first year following birth, the child seemed to be developing normally. However, when the child was around 14 months old, she began experiencing progressively worsening myoclonic seizures. Over the next few months, the seizures continued to worsen. The child did receive treatment, which seemed to reduce seizure frequency. Yet the child also showed signs of balance and coordination problems, as well as development regression. 

Discovering the Missense Mutation for Angelman Syndrome

After testing, the child was found to have a novel UBE3A missense mutation which researchers called Leu614Pro. This mutation caused proline (an amino acid) to be placed at protein change position 614 instead of leucine. At position 1,841, the patient had cysteine instead of thymine.

Researchers wanted to understand how these changes and this mutation actually affected the body. They ran a series of computer modeling tests. Altogether, these tests found that the mutated Leu614Pro protein was unable to enter into a “closed” configuration that non-mutated UBE3A protein used to interact with ubiquitin, another protein. This is similar to Met589Lys, another missense mutation associated with Angelman syndrome.

Because the mutated proteins are unable to enter into this configuration, researchers believe that they prevent the binding and transfer of ubiquitin, causing some of the symptoms and characteristics of Angelman syndrome. 

Missense Mutations: A Brief Overview

The National Cancer Institute (NCI) describes a missense mutation as: 

a genetic alteration in which a single base pair substitution alters the genetic code in a way that produces an amino acid that is different from the usual amino acid at that position. Some missense variants will alter the function of the protein.

You may also learn more about missense variants, causes, and more through this helpful Osmosis from ELSEVIER primer

What is Angelman Syndrome?

Angelman syndrome is a rare neuro-genetic disorder typically caused by a defective or missing UBE3A gene on chromosome 15. Because many people with Angelman syndrome do not have a family history of this disorder, doctors and researchers are unsure what prompts this genetic change. While this disorder does not have a cure, those with this condition often live a normal lifespan. Symptoms and characteristics typically appear between ages 1-4. These can (but do not always) include:

  • Minimal to no speech
  • Happy, excitable personalities 
  • Developmental delays
  • Sleep disorders
  • Subtle tremors in the arms and legs
  • Smaller than average head size
  • Scoliosis
  • Feeding difficulties in younger children or obesity in older children 
  • Slow, stiff, or jerky walking
  • Ataxia (balance and coordination issues)
  • Tongue thrusting, hand flapping, or uplifted arms while walking
  • Seizures
Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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