title: De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy.
abstract: De novo GRIN1 mutations have recently been shown to cause severe intellectual disability, hypotonia, hyperkinetic and stereotyped movements, and epilepsy. We report two new cases of severe early onset encephalopathy associated with hyperkinetic and oculogyric-like movements, caused by mutations in the GRIN1 gene; both were identified by whole exome sequencing. One of the patients harbored the novel mutation p.Ser688Tyr and the other patient harbored the p.Gly827Arg mutation, which was previously reported in three patients. In silico studies suggested that the p.Se688Tyr mutation results in disruption of NMDA ligand binding and the p.Gly827Arg mutation results in disrupted gating of the ion channel. Our study highlights the importance of GRIN1 mutations in the etiology of isolated cases of early onset encephalopathy, and the valuable role of whole exome sequencing in identifying these mutations.
authors.affiliation: Pediatric Department B, Emek Medical Center, Afula, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Zehavi
authors.affiliation: Institute of Human Genetics and Metabolic Diseases, Galilee Medical Center, Nahariya, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Department of Biotechnology and Food Engineering, Technion, Haifa, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Zehavi
authors.affiliation: Clalit Health Services, Haifa, Israel.
authors.forename: Muhammad Abu
authors.initials: MA
authors.lastname: Rashid
authors.affiliation: Pediatric Neurology Unit, Schneider Children's Medical Center, Petach Tikva, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.affiliation: Clalit Health Services, Haifa, Israel.
authors.forename: Banan
authors.initials: B
authors.lastname: Jabur
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Pediatric Department B, Emek Medical Center, Afula, Israel; Rappaport School of Medicine, Technion, Haifa, Israel. Electronic address: spiegelr@zahav.net.il.
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
mesh_terms: D001665:Binding Sites; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000175:diagnosis / Q000235:genetics*; D015640:Ion Channel Gating; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: C485668:GRIN1 protein, human; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate
keywords: De novo mutation; Early onset encephalopathy; GRIN1; Oculogyric movements