How seizures, epilepsy and other brain malformations develop from genetic variants is not fully understood, but a new National Institutes of Health (NIH) award will pave the way toward understanding the cause and potentially lead to new therapies.
New (non-inherited) genetic variants can arise as cells divide during embryonic development and give rise to mosaicism—sets of cells that are genetically different from one another. Such variants have been shown to cause seizures and brain malformations. The abnormal mosaic brain tissue can sometimes be surgically removed to treat the seizures caused by these genetic variants.
This new NIH award of more than $420,000 will allow for the deep study of individual cells comprising these brain tissue specimens to better understand how these genetic variants cause disease and how we can better treat these conditions.
This proof-of-concept study will look at tissue comprised of a mixture of cells with and without a genetic variant that causes a rare brain malformation to study the effect of the variant on gene regulation in different types of brain cells.
This project is led by principal investigator Erin Heinzen, Pharm.D., ‘01, Ph.D. ‘04, associate professor at the UNC Eshelman School of Pharmacy in the Division of Pharmacotherapy and Experimental Therapeutics (DPET) with a joint appointment in the UNC Department of Genetics, in partnership with co-investigator Di Wu, Ph.D., associate professor in the Department of Biostatistics and associate professor at the UNC School of Dentistry.
“Our lab studies the role of somatic variants in epilepsy,” said Heinzen. “This award will allow us to continue to study the effects of the variants in human brain tissue and identify cell type specific effects that may help us better understand the specific molecular disruptions that lead to disease.”
The team hypothesizes that their study will reveal reproducible convergent and divergent cell-type-specific disease mechanisms across individuals with the same pathogenic variants and across genes implicated in the same brain malformation. If successful, they will establish a powerful research approach the leverages somatic mosaicism to inform cell types involved in disease, identify the functional changes that accompany neurological and neuropsychiatric diseases and illuminate new therapeutic strategies.
“The long-term goal of the work is to illuminate transcriptomic changes associated with the pathogenic variant that may direct us toward novel and targeted therapies,” said Heinzen.
This article originally appeared in UNC School of Medicine’s Vital Signs HERE.