GRIN disorders are rare genetic conditions that affect one of the seven GRIN genes that encode NMDA receptor subunits, which mediate excitatory synaptic transmission in the brain. Most cases are de novo missense mutations that are linked to developmental delays and autism spectrum disorder (ASD), in addition to intellectual disabilities, epilepsy, hypotonia, constipation, feeding difficulties, cortical visual impairment, dystonia, language difficulties, behavioral disturbances and sleep issues. The natural history, incidence and full spectrum of GRIN disorder severity are not fully understood.
Current treatment options exist only for managing symptoms, and there are no FDA-approved GRIN-specific therapies. An understanding of the variability among individuals with GRIN disorders with regard to functional status of the NMDA receptor is essential to designing effective therapeutic strategies1. Future clinical trials will require assessment of functional status as part of inclusion/exclusion criteria. Likewise, some appreciation of how symptoms change over time is needed to understand when to intervene and whether interventions are beneficial.
Stephen Traynelis and colleagues plan to obtain clinical and longitudinal data for individuals with GRIN variants in addition to functional data on these variants. The information will be collated into a single database. Such a database will be made available to other researchers and family groups and is expected to provide valuable information to help stratify individuals, allowing the selection of homogeneous GRIN disorder subpopulations for future clinical studies and trials.
The project will use current GRIN registries associated with Johannes Lemke, Tim Benke and Jennifer Bain to collect clinical and longitudinal information for GRIN participants. Stephen Traynelis and Steven Finkbeiner will functionally characterize variants found in people with GRIN disorders in vitro, using both voltage clamp electrophysiological assays and an automated robotic high-throughput single-cell confocal imaging platform that allows measures of cellular phenotypes. This technology has been previously used to elucidate disease-related phenotypes in neurons derived from induced pluripotent stem cells from patients with Huntington’s disease2.
The complexity of genetic disorders involving neurocognitive impairments due to missense variants that increase or decrease specific protein functions requires both functional and clinical data to effectively pursue new therapeutic strategies. Completion of this study is expected to create a model platform for similar genetic conditions and will be useful in determining the role of functional variation, natural history and clinical outcome measures.
- Impact of NR2B mutations on NMDA receptors and synapse formation
- High-throughput functional annotation of human SCN2A variants
- Functional evaluation and curation of SCN2A variants associated with autism
- Electrophysiological consequences of SCN2A mutations found in autism
- Building phenotypic maps based on neuronal activity and transcriptional profiles in human cell models of syndromic forms of ASD