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Brain-Specific Somatic Mutations Detected in Epilepsy-Causing Overgrowth Condition

NEW YORK (GenomeWeb News) – A Massachusetts-led research group has uncovered brain tissue-specific somatic mutations behind a developmental condition characterized by extensive enlargement in one half of the brain, which often causes intellectual disability and severe epilepsy.

As they reported online today in Neuron, the researchers used microarrays, quantitative PCR, and targeted sequencing to look for somatic mutations in surgically removed brain tissue samples from eight individuals with this brain overgrowth condition, called hemimegalencephaly. Two samples contained duplications affecting large swaths of chromosome 1, while another harbored an activating mutation in AKT3, a gene found within the same stretch of chromosome 1.

"Our data suggest that spontaneous mutations resulting in abnormal activation of AKT3 contribute to overgrowth of one-half of the brain," senior author Christopher Walsh, a genetics, neurology, and pediatrics researcher with Children's Hospital Boston, Harvard University, and the Broad Institute, said in a statement.

The HMG-associated alterations were not present in blood samples from the same individuals, when available, suggesting they occur during brain development. And Walsh noted that the architecture and the size of the affected region might partly depend on the stage of development when this somatic mutation arises.

There have been a few examples of somatic mutations that affect only certain tissues or subsets of cells within a given tissue, researchers noted. So far though, they explained, "it has been essentially impossible to study potential roles of mutations that are limited to brain cells, because such mutations are by definition absent from blood and other tissues typically available for genetic study."

Even so, the team suspected that such brain-centered somatic mutations might be at play in HMG, a condition in which just one hemisphere in the brain becomes dramatically enlarged.

It was possible to test that theory directly, since the severe epileptic seizures associated with HMG are sometimes treated by surgically removing the affected brain region. For the current study, for instance, researchers had access to resected brain tissue samples from eight children with HMG.

They relied on Affymetrix 100K SNP arrays to do copy number profiling in six of these samples, identifying large chromosome 1 duplications in brain samples from two of the children — alterations that were subsequently verified by qPCR.

Among the genes in this region, AKT3 appeared to be the most promising potential culprit in HMG, study authors explained, since its absence has been linked to diminished brain size. In addition, they noted, a mutation that activates a related gene, AKT1, can cause a skin and bone overgrowth condition called Proteus syndrome.

When researchers did targeted sequencing of the AKT3 gene in the six other HMG brain samples, they found an activating mutation in AKT3 in one of the samples that was akin to activating AKT1 mutation reported in Proteus syndrome.

Meanwhile, the team's follow-up experiments using fetal and mouse brain supported the notion that AKT3 plays a pivotal role in neurogenesis, brain development, and growth.

"Our data suggest that activation of AKT3, either by duplication or by point mutation, contributes to hemispheric brain overgrowth," they wrote.

Rather than turning up throughout the body, though, their results suggest that the alterations are limited to brain tissue in at least some of the HMG cases.

A matched blood sample was not available for one of the children with chromosome 1 duplications, researchers noted. But the other chromosome 1 duplication and the AKT3 activating mutation both appear to be de novo somatic mutations that occurred in the brain but were absent from corresponding blood samples.

"[T]o our knowledge, this is the first disease attributed to mutations that are limited to brain tissue," Walsh said. "There are other epilepsies and neuropsychiatric diseases that are associated with spontaneous mutations and are therefore also candidates for these sorts of 'brain-only' mutations."

Identifying such mutations in other conditions is expected to be challenging, the study authors conceded, since brain tissue is typically unavailable for testing. Even so, they argued that such changes could become easier to detect as the amount of input DNA needed for CNV analyses and sequencing studies decreases.