New UBE3A Missense Mutation in Angelman Child Described

Angelman syndrome is attributable to missense mutations in about 5% of cases

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

Share this article:

Share article via email
ube3a mutation | Angelman Syndrome News | illustration of DNA

A new mutation in the UBE3A gene associated with Angelman syndrome was described in a recent report and modeling studies suggest the modification interferes with the function of the UBE3A protein by decreasing its ability to interact with ubiquitin, another protein.

The study, “Studying Disease-Associated UBE3A Missense Variants Using Enhanced Sampling Molecular Simulations,” was published in ACS Omega.

Angelman syndrome is caused by mutations in the UBE3A gene, which provides instructions for making the UBE3A (ubiquitin-protein ligase E3A) protein. The most common type of Angelman-causing mutation is a deletion of the part of chromosome 15 that houses the gene.

In about 5% of cases, Angelman is attributable to missense mutations — when a single nucleotide, one of the “letters” of the genetic code, is altered, resulting in a change in one amino acid in the protein that’s generated when the gene is “read.” Amino acids are the building blocks of proteins.

Recommended Reading
genetic mosaicism in Angelman | Angelman Syndrome News | illustration of DNA strand

New UBE3A Mutation Linked to Severe Angelman in 2 Chinese Sisters

While missense mutations have been linked with Angelman, the exact biochemical consequences of these mutations on the function of the UBE3A protein are often obscure.

Scientists in Australia described the case of a child with a missense mutation in UBE3A that has never been reported before. The child’s development was mostly normal during the first year of life, but at 14 months she began to have myoclonic seizures marked by jerky, spasmodic muscle movements.

The seizures continued to worsen over the subsequent months and the child’s development started regressing at 16 months. She was treated with the anti-seizure medications Klonopin (clonazepam) and Keppra (levetiracetam), which reduced their frequency and improved development to some extent, though she continued to struggle with balance.

A number of diagnostic tests were undertaken and targeted epilepsy gene panel testing revealed a mutation in the UBE3A gene. At the 1,841st position in the genetic code where there is typically the nucleotide thymine (“T”) the patient had a cysteine (“C”) instead.

Analyses of the genetic code suggested this was a missense mutation that would result in the amino acid proline being placed at position 614 in the protein chain where there is normally another amino acid called leucine. Computer modeling tests were conducted to explore the consequences of this mutation, dubbed “Leu614Pro” for its effect on the UBE3A protein.

Results showed the wild-type (non-mutated) UBE3A protein could take on a particular “closed” configuration that’s needed for it to interact with another protein called ubiquitin, which is important for the normal function of UBE3A. The Leu614Pro mutated protein could not enter this configuration.

The research team also studied two other missense mutations: Met589Lys, known to cause Angelman syndrome, and Ile755Thr, which is not known to cause disease. Only the Angelman-associated mutation interfered with the “closed” configuration of the UBE3A protein, results showed.

“To summarize, wild-type UBE3A and the Ile755Thr variant feature low-energy closed (putative ubiquitin-binding) states, suggesting normal ubiquitin transfer function, while both variants identified in individuals with [Angelman] (Leu614Pro and Met589Lys) lost access to the closed (putative ubiquitin-binding) state and thus may fail to efficiently bind and transfer ubiquitin,” the researchers concluded.