NMDA receptors and brain malformations: GRIN1-associated polymicrogyria

Ion channels and brain malformations. When the “channelopathy” concept first emerged – the idea that dysfunction of neuronal ion channels leads to neurological disease including epilepsy – it seemed implausible that such dysfunction could lead to malformations of cortical development. However, recent research has suggested that ion channel dysfunction may indeed be linked with brain malformations. In 2017, we saw convincing evidence that germline de novo variants in GRIN2B can cause malformations of cortical development. Some suggestive, but less conclusive, evidence has also linked SCN1A and SCN2A to brain malformations. Now Fry and collaborators demonstrate that de novo pathogenic variants in GRIN1 can also cause significant polymicrogyria, expanding the phenotypic spectrum of GRIN1-related disorders. As a disclaimer, I am also a co-author on the publication by Fry and collaborators.

Clustering of GRIN1 variants. A schematic diagram of the GRIN1 protein, showing the localization of polymicrogyria (PMG) associated GRIN1 variants on the top in red and non-PMG associated GRIN1 variants on the bottom in yellow. PMG-associated variants cluster in the M3 and S2 regions of the protein, which are important in channel gating and glycine binding. Over 50% of non-PMG associated variants are located in the transmembrane M4 helix, where no PMG-associated variants have been reported. Some GRIN1 variants have been reported in both patients with and without polymicrogyria. However, these patients have only had CT scans, which is not capable of detecting polymicrogyria.

GRIN1-related polymicrogyria. Fry and collaborators have identified de novo pathogenic variants in GRIN1 in 11 individuals with significant malformations of cortical development and associated neurodevelopmental disorders. MRI features included extensive bilateral cortical malformations, most consistent with polymicrogyria primarily in the frontal and parietal regions. One of the de novo GRIN1 variants was identified in a 22-week gestational age male fetus, with abnormal thinning and sulcation of the cerebral cortex, hypoplastic corpus callosum, and ventriculomegaly. This suggests that GRIN1-related cortical malformations may be detectable prenatally.

Gain-of-function vs. loss-of-function. Functional analysis polymicrogyria-associated GRIN1 variants identified an increased sensitivity to NMDA receptor agonists glycine and glutamate, consistent with a strong gain-of-function effect. This is in stark contrast to previously reported GRIN1 variants in patients without polymicrogyria, which were found to have significant dominant-negative and loss-of-function properties. Although this gain-of-function vs. loss-of-function dichotomy may be an oversimplification, it does suggest a correlation between the functional consequence of the GRIN1 variant and the resulting phenotype. Over-activation of the NMDA receptor may result in malformations of cortical development while loss of NMDA receptor function will result in a neurodevelopmental disorder without brain malformation. Although the mechanism whereby NMDA receptor gain-of-function results in neuronal migration defects is still not understood, one hypothesis is that the excitotoxic effects of NMDA receptor hyperactivation may lead to cell death during fetal brain development, which could lead to migrational defects in developing neurons.

Genotype-phenotype correlations. Comparison of GRIN1 variants in patients with polymicrogyria compared to patients without polymicrogyria showed that these variants cluster in different parts of the protein. The polymicrogyria-associated GRIN1 variants were highly clustered in the S2 domain and adjacent M3 helix regions of the GRIN1 protein. The S2 domain forms part of the glycine-binding domain. Glycine is an NMDA receptor activator. The polymicrogyria-associated variants in the M3 region were in a motif known to control NMDA receptor gating. This S2/M3 clustering of polymicrogyria-associated variants in GRIN1 is similar to what is seen in GRIN2B. In contrast, over 50% of previously reported GRIN1 variants in people without polymicrogyria are located in the M4 segment, where no polymicrogyria-associated variants were found.

Implications for precision medicine. It is likely too early to say whether or not these findings will directly influence precision medicine decisions for families affected by GRIN1-related disorders. However, the suggestion of genotype-phenotype correlations does provide additional evidence that may help in a clinical context. This research suggests that gain-of-function variants are most likely associated with a brain malformation phenotype whereas individuals with GRIN1-related disorders without brain malformations are more likely to have loss-of-function variants. Memantine, which is an NMDA receptor blocker, would theoretically be more useful for people with a confirmed gain-of-function variant. However, additional research is needed to investigate the usefulness of memantine in a clinical context, particularly for patients who have an underlying brain malformation.

Katie Helbig

Katie Helbig is a licensed genetic counselor with the Division of Neurology at the Children’s Hospital of Philadelphia, where she researches the role of genetic factors in childhood onset epilepsies and related neurodevelopmental disorders and provides genetic counseling to families in the Neurogenetics Clinic. She has a longstanding interest in epilepsy genetics, with previous experience in research, bioethics, and genomic diagnostics. She is co-chair of EpiGC, a member of the ClinGen Epilepsy Gene Curation Expert Panel, and member of the ILAE Task Force on Clinical Genetic Testing in the Epilepsies.