{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:45:54Z","timestamp":1790401554328,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,4,10]],"date-time":"2015-04-10T00:00:00Z","timestamp":1428624000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Ministry of Health, Labour and Welfare of Japan"},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["25293085"],"award-info":[{"award-number":["25293085"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["25293235"],"award-info":[{"award-number":["25293235"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["26670505"],"award-info":[{"award-number":["26670505"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["13313587"],"award-info":[{"award-number":["13313587"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["24591500"],"award-info":[{"award-number":["24591500"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["26330331"],"award-info":[{"award-number":["26330331"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Strategic Research Program for Brain Sciences","award":["11105137"],"award-info":[{"award-number":["11105137"]}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","doi-asserted-by":"crossref","award":["12024421"],"award-info":[{"award-number":["12024421"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Recently, de novo mutations in <jats:italic><jats:styled-content style=\"fixed-case\">GRIN<\/jats:styled-content>1<\/jats:italic> have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (<jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with <jats:italic><jats:styled-content style=\"fixed-case\">GRIN<\/jats:styled-content>1<\/jats:italic> mutations, allowing us to investigate the phenotypic spectrum of <jats:italic><jats:styled-content style=\"fixed-case\">GRIN<\/jats:styled-content>1<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eighty\u2010eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset &lt;1\u00a0year were analyzed by <jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>. The effect of mutations on <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate (NMDA) receptors was examined by mapping altered amino acids onto three\u2010dimensional models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified four de novo missense <jats:italic><jats:styled-content style=\"fixed-case\">GRIN<\/jats:styled-content>1<\/jats:italic> mutations in 4 of 88 patients with unclassified <jats:styled-content style=\"fixed-case\">EOEE<\/jats:styled-content>s. In these four patients, initial symptoms appeared within 3\u00a0months of birth, including hyperkinetic movements in two patients (2\/4, 50%), and seizures in two patients (2\/4, 50%). Involuntary movements, severe developmental delay, and intellectual disability were recognized in all four patients. In addition, abnormal eye movements resembling oculogyric crises and stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression\u2010burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G&gt;A) with a mutant allele frequency of 16% (in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3\/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Clinical features of de novo <jats:italic><jats:styled-content style=\"fixed-case\">GRIN<\/jats:styled-content>1<\/jats:italic> mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that <jats:italic><jats:styled-content style=\"fixed-case\">GRIN<\/jats:styled-content>1<\/jats:italic> mutations cause encephalopathy resulting in seizures and movement disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12987","type":"journal-article","created":{"date-parts":[[2015,4,10]],"date-time":"2015-04-10T23:42:03Z","timestamp":1428709323000},"page":"841-848","source":"Crossref","is-referenced-by-count":95,"title":["<i><scp>GRIN<\/scp>1<\/i> mutations cause encephalopathy with infantile\u2010onset epilepsy, and hyperkinetic and stereotyped movement disorders"],"prefix":"10.1111","volume":"56","author":[{"given":"Chihiro","family":"Ohba","sequence":"first","affiliation":[{"name":"Department of Human Genetics Graduate School of Medicine Yokohama City University Yokohama Japan"},{"name":"Department of Clinical Neurology and Stroke Medicine Yokohama City University Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Shiina","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Graduate School of Medicine Yokohama City University Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tohyama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Epilepsy Center Nishi\u2010Niigata Chuo National Hospital Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Haginoya","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Takuto Rehabilitation Center for Children Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tally","family":"Lerman\u2010Sagie","sequence":"additional","affiliation":[{"name":"Metabolic Neurogenetic Clinic Wolfson Medical Center Holon Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Osaka Medical Center Research Institute for Maternal and Child Health Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubov","family":"Blumkin","sequence":"additional","affiliation":[{"name":"Metabolic Neurogenetic Clinic Wolfson Medical Center Holon Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorit","family":"Lev","sequence":"additional","affiliation":[{"name":"Metabolic Neurogenetic Clinic Wolfson Medical Center Holon Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souichi","family":"Mukaida","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology National Hospital Organization Utano Hospital Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihito","family":"Nozaki","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shiga Medical Center for Children Shiga Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsugu","family":"Uematsu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Tohoku University School of Medicine Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Onuma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Ekoh\u2010Ryoikuen Sendai 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