Aggregation Consortium (ExAC) combines sequences for the
protein-coding parts of the genome from more than 60,000 people into a
database that continues to expand.
The study of human genetics has often focused on mutations that cause
disease. When it comes to genetic variations in healthy people,
scientists knew they were out there, but didn't have a full picture of
‘A deep dive into the Exome Aggregation Consortium (ExAC) data to explore the link between NMDA receptor variation and epilepsy has been published in the American Journal of Human Genetics.’
That is changing with the emergence of resources such as the Exome
At Emory, the labs of Stephen Traynelis and Hongjie Yuan have
published an analysis of ExAC data, focusing on the genes encoding two
NMDA receptor subunits, GRIN2A and GRIN2B. These receptors are central
to signaling between brain cells, and rare mutations in the
corresponding genes cause epilepsy (GRIN2A) or intellectual disability
(GRIN2B). GRIN2B mutations have also been linked with autism spectrum
The new paper in the American Journal of Human Genetics
makes a deep dive into ExAC data to explore the link between normal
variation in the healthy population and regions of the proteins that
harbor disease-causing mutations.
In addition, the paper provides a detailed look at how 25 mutations
that were identified in individuals with neurologic disease actually
affect the receptors. For some patients, this information could
potentially guide anticonvulsant treatment with a repurposed Alzheimer's
medication. Also included are three new mutations from patients
identified by whole exome sequencing, one in GRIN2A and two in GRIN2B.
"This is one of the first analyses like this, where we're mapping
the spectrum of variation in a gene onto the structure of the
corresponding protein," says Traynelis, professor of pharmacology
at Emory University School of Medicine. "We're able to see that the
disease mutations cluster where variation among the healthy population
Postdoctoral fellow Sharon Swanger is first author of the
paper, and Yuan, assistant professor of pharmacology, is
It's not always obvious, looking at the sequence of a given
mutation, how it's going to affect NMDA receptor function. Only
introducing the altered gene into cells and studying protein function in
the lab provides that information, Traynelis says.
NMDA receptors are complicated machines: mutations can affect how
well they bind their ligands (glutamate and glycine), how they open and
shut, or how they are processed onto the cell surface. On top of that
complexity, mutations that make the receptors either stronger or weaker
can both lead the brain into difficulty; within each gene, both types of
mutation are associated with similar disorders.
With some GRIN2A mutations, the functional changes identified in the
lab were quite strong, but the effect on the brain was less dramatic
(mild intellectual disability or speech disorder), suggesting that other
genetic factors contribute to outcomes.
Traynelis and Yuan previously collaborated with the NIH's
Undiagnosed Disease Program to show that the Alzheimer's medication
memantine can be repurposed as an anticonvulsant for a child with
intractable epilepsy coming from a mutation in the GRIN2A gene.
Memantine is an NMDA receptor antagonist and was aimed at
counteracting the overactivation of the receptor caused by the mutation.
Memantine has also been used to treat children with epilepsy associated
with mutations in the related GRIN2D gene.
However, memantine doesn't work on all activating mutations, and could
have effects on the unmutated NMDA receptors in the brain as well.
Traynelis reports that his clinical colleagues are developing
guidelines for physicians on the use of memantine for children with GRIN