3-gene Signature May Help in Diagnosis of Angelman: New Study

Activity levels of 3 genes may be used as disease biomarker

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The expression, or activity, of a trio of genes are altered in the nerve cells of people with Angelman syndrome, a new study suggests, and researchers say that assessing these levels may help in disease diagnosis.

Two of the genes, ADAMTS2, and SLC30A8, had lower-than-normal expression in nerve cells, while the third, ACTN1, was found to have activity that was higher than normal.

A score developed by assessing levels of these three genes “could serve as a biomarker to distinguish AS [Angelman syndrome] from normal patients,” according to the researchers.

“This study may provide [a] new approach for diagnosing patients with [Angelman syndrome] and helping to develop novel therapies in treating [Angelman] patients,” the team wrote.

The study, “Identification of key biomarkers in Angelman syndrome by a multi-cohort analysis,” was published in Frontiers in Medicine.

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Finding new Angelman biomarkers

Angelman syndrome is caused by mutations that affect the maternal UBE3A gene. Genetic testing can identify the disease-causing mutation in about 90% of patients. But for nearly one in 10 people with Angelman-like symptoms, genetic testing is inconclusive.

Finding new Angelman biomarkers — objective biological measurements that can differentiate people with the neurological disorder from those without — may be useful for confirming a diagnosis in these patients.

In this study, a team of scientists at Tongji Medical College, in China, analyzed gene expression data in cell models. Gene expression refers to the extent that individual genes are being “read” in the cell to produce proteins.

For these analyses, the researchers used prior data collected from iPSC-derived neurons. In this type of model, easily accessible cells (e.g., skin or blood cells) are collected from patients, then are “reverse engineered” into stem cells via a specific set of biochemical manipulations.

Then, these stem cells — called induced pluripotent stem cells, or iPSCs — are given further cues so that they grow into neurons (nerve cells).

The researchers conducted initial gene expression analyses using data from a total of 48 iPSC-derived neurons. These results revealed that the gene ACTN1 was up-regulated in Angelman cells, while the genes ADAMTS2 and SLC30A8 were down-regulated in the cells.

The ACTN1 gene provides instructions for making a protein that helps build the cytoskeleton — a network of proteins inside of cells that helps to maintain the structure of cells.

The team noted that, to their knowledge, this is the first published report of abnormal ACTN1 expression in Angelman syndrome.

The ADAMTS2 gene encodes a protein involved in maintaining the extracellular matrix, a protein network outside of cells that helps maintain tissue function. The protein encoded by the SLC30A8 gene helps regulate the movement of zinc.

“It is likely that Zinc transporters … play a direct role” in Angelman, the researchers noted.

The team then validated these gene expression findings using data from six human embryonic stem cell lines. Consistent with the initial findings in iPSC-derived neurons, results showed that these three genes were differentially expressed in Angelman cells.

An expression signature based on the three genes was able to distinguish between Angelman and non-Angelman cells with 100% accuracy in these cell lines.

“We developed a model for [Angelman syndrome] scores using these three genes at the same time,” the researchers wrote. They dubbed their model “the AS signature,” noting its “three diagnostic biomarkers.”

The team emphasized a need for further research to confirm these findings, and to investigate the potential roles of these genes in Angelman disease processes.