Study adds two new genetic variants to the list of glutamate receptor mutations

Researchers from Northwestern Medicine distinguished different variants of the gene GRIK2 that induces nonsyndromic neurodevelopmental disorder (NDD). The research was published in the American Journal of Human Genetics.

Geoffrey Swanson, PhD, professor of Pharmacology, was senior author of the study published in the American Journal of Human Genetics. Image Credit: Northwestern University Feinberg School of Medicine.

The observations add two novel genetic variants to an expanding list of glutamate receptor mutations that induce neurodevelopmental disorders, says Geoffrey Swanson, PhD, professor of Pharmacology and senior author of the study.

When new variants are reported, they are incorporated into bioinformatics analyses. It’s like a snowball effect—the more variants are reported, the more likely it will be picked up in new patients.”

Geoffrey Swanson, Study Senior Author and Professor, Pharmacology, Northwestern University Feinberg School of Medicine

GRIK2 codes for a single member of a family of kainate receptors (KARs), which are glutamate-gated ion channels that help sustain the inhibitory and excitatory balance in the brain. An earlier study has revealed that bi-allelic loss of function mutations in GRIK2 can result in NDD; however, there is scarce knowledge about the mono-allelic variants and their link to neurodevelopmental disorders.

The scientists in their recent research briefed on 11 individuals with de novo, mono-allelic mutations in GRIK2. Six individuals had an earlier recorded variant—a guanine-to-adenine point mutation—and five individuals had related but new variants.

Significantly, patient phenotypes were alike among the individuals with similar variants but showed significant differences from patients with distinct variants. For instance, certain patients with the newly discovered variant had what seemed to be the start of neurodegeneration, indicated by white matter abnormalities that increased eventually.

These variants, even though close in genetic distance, can have a significant effect on the character or severity of NDD, states Swanson.

These subtle differences really can have a massive consequence on the outcome of the kids.”

Geoffrey Swanson, Study Senior Author and Professor, Pharmacology, Northwestern University Feinberg School of Medicine

Characterizing the specific variants and their phenotypes is important, as these observations would be combined to databases for rare genetic diseases, say the authors. This could help clinicians and families comprehend their child’s condition and feasible trajectory.

These databases are important so neurologists around the world can compare notes about patients, what parents can expect, and any possible treatments if they become available.”

Geoffrey Swanson, Study Senior Author and Professor, Pharmacology, Northwestern University Feinberg School of Medicine

Swanson says, in the future, he anticipates investigating numerous GRIK2 variants that can induce NDD and provide platforms to better analyze the complex neural circuitry affected by these mutations.

Swanson also stated, “In order to really understand what’s going on at the level of synapses or circuits, we need to model those circuits and see how GRIK2 affects systems such as neuronal excitability.”