MOL Highlight: Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy
Ionotropic glutamate receptors play important roles in normal brain development and are implicated in a wide range of neurologic disorders, including epilepsy. This paper investigates the molecular consequences of a somatic mutation identified in a child with profound global developmental delay and refractory epilepsy. The mutant receptor showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors, prolonged synaptic-like response time course, increased single-channel mean open time, and increased channel open probability. The results are therefore consistent with this mutation causing overactivation and driving neuronal hyperexcitability. Molecular modeling further suggests that this mutation weakens the interaction between the transmembrane helices of the receptor and increases the dynamics of important linker regions of the receptor, leading to enhanced function. A number of glutamate receptor-targeted drugs, including U.S. Food and Drug Association–approved channel blockers, were evaluated for their ability to inhibit receptors containing this mutation as a first step towards exploring the potential for rescue pharmacology and personalized medicine.
See the article by Chen et al. at Molecular Pharmacology April 2017, 91 (4) 317-330; DOI: https://doi.org/10.1124/mol.116.106781