title: GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.
abstract: OBJECTIVE
  Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations.
  
  
  METHODS
  Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset <1 year were analyzed by WES. The effect of mutations on N-methyl-D-aspartate (NMDA) receptors was examined by mapping altered amino acids onto three-dimensional models.
  
  
  RESULTS
  We identified four de novo missense GRIN1 mutations in 4 of 88 patients with unclassified EOEEs. In these four patients, initial symptoms appeared within 3 months 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-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA 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.
  
  
  CONCLUSIONS
  Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders.
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.|Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
authors: Chihiro
authors: C
authors: Ohba
authors: Department of Biochemistry, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Masaaki
authors: M
authors: Shiina
authors: Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan.
authors: Jun
authors: J
authors: Tohyama
authors: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan.
authors: Kazuhiro
authors: K
authors: Haginoya
authors: Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel.
authors: Tally
authors: T
authors: Lerman-Sagie
authors: Department of Medical Genetics, Osaka Medical Center, Research Institute for Maternal and Child Health, Osaka, Japan.
authors: Nobuhiko
authors: N
authors: Okamoto
authors: Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel.
authors: Lubov
authors: L
authors: Blumkin
authors: Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel.
authors: Dorit
authors: D
authors: Lev
authors: Department of Pediatric Neurology, National Hospital Organization Utano Hospital, Kyoto, Japan.
authors: Souichi
authors: S
authors: Mukaida
authors: Department of Pediatrics, Shiga Medical Center for Children, Shiga, Japan.
authors: Fumihito
authors: F
authors: Nozaki
authors: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors: Mitsugu
authors: M
authors: Uematsu
authors: Department of Pediatrics, Ekoh-Ryoikuen, Sendai, Japan.
authors: Akira
authors: A
authors: Onuma
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Hirofumi
authors: H
authors: Kodera
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Mitsuko
authors: M
authors: Nakashima
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Yoshinori
authors: Y
authors: Tsurusaki
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Noriko
authors: N
authors: Miyake
authors: Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
authors: Fumiaki
authors: F
authors: Tanaka
authors: Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata, Japan.
authors: Mitsuhiro
authors: M
authors: Kato
authors: Department of Biochemistry, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Kazuhiro
authors: K
authors: Ogata
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Hirotomo
authors: H
authors: Saitsu
authors: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Naomichi
authors: N
authors: Matsumoto
mesh_terms: D000293:Adolescent; D001927:Brain Diseases / Q000150:complications / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006948:Hyperkinesis / Q000150:complications / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D019956:Stereotypic Movement Disorder / Q000150:complications / Q000235:genetics*
chemical_list: C485668:GRIN1 protein, human; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Encephalopathy; GRIN1; Movement disorders; Neurotransmitter disorders; Seizure