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Hum Mutat
2019 Dec 01;4012:2393-2413. doi: 10.1002/humu.23895.
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De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.
Li J, Zhang J, Tang W, Mizu RK, Kusumoto H, XiangWei W, Xu Y, Chen W, Amin JB, Hu C, Kannan V, Keller SR, Wilcox WR, Lemke JR, Myers SJ, Swanger SA, Wollmuth LP, Petrovski S, Traynelis SF, Yuan H.
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N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in the central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here, we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M2 re-entrant loop, a region that lines the pore and is intolerant to missense variation. These de novo variants were identified in children with a set of neurological and neuropsychiatric conditions. Evaluation of the receptor cell surface expression, pharmacological properties, and biophysical characteristics show that these variants can have modest changes in agonist potency, proton inhibition, and surface expression. However, voltage-dependent magnesium inhibition is significantly reduced in all variants. The NMDARs hosting a single copy of a mutant subunit showed a dominant reduction in magnesium inhibition for some variants. These variant NMDARs also show reduced calcium permeability and single-channel conductance, as well as altered open probability. The data suggest that M2 missense variants increase NMDAR charge transfer in addition to varied and complex influences on NMDAR functional properties, which may underlie the patients' phenotypes.
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R01 NS036654 NINDS NIH HHS , R01 HD082373 NICHD NIH HHS , R01 NS088479 NINDS NIH HHS , R01 EY016979 NEI NIH HHS , R01HD08237 Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH), R24 NS092989 NINDS NIH HHS , R35 NS111619 NINDS NIH HHS
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