1. GRIN2D variants in three cases of developmental and epileptic encephalopathy
- Author
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Naomi Tsuchida, Yu Kobayashi, Vigneswari Ganesan, Kazuhiro Ogata, Kyoko Hoshino, Naomichi Matsumoto, Noriko Miyake, Atsushi Takata, Mitsuhiro Kato, Jun Tohyama, Masaaki Shiina, Satomi Mitsuhashi, Kazue Kimura, Mitsuko Nakashima, Keisuke Hamada, Hirotomo Saitsu, Keng Wee Teik, Satoko Miyatake, and Takeshi Mizuguchi
- Subjects
0301 basic medicine ,Male ,Adolescent ,Genotype ,Protein Conformation ,Developmental Disabilities ,Central nervous system ,Biology ,Molecular Dynamics Simulation ,Bioinformatics ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,Epilepsy ,Structure-Activity Relationship ,Genetics ,medicine ,Missense mutation ,Humans ,Amino Acid Sequence ,Receptor ,Child ,Genetics (clinical) ,Exome sequencing ,Ion channel ,Alleles ,Brain ,Genetic Variation ,Electroencephalography ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Mutation ,NMDA receptor ,Female ,Function (biology) - Abstract
N-methyl-d-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy. All altered residues were highly conserved across vertebrates and among the four GluN2 subunits. Structural consideration indicated that all three variants are probably to impair GluN2D function, either by affecting intersubunit interaction or altering channel gating activity. We assessed the clinical features of our three cases and compared them to those of the two previously reported GRIN2D variant cases, and found that they all show similar clinical features. This study provides further evidence of GRIN2D variants being causal for epilepsy. Genetic diagnosis for GluN2-related disorders may be clinically useful when considering drug therapy targeting NMDA receptors.
- Published
- 2018