title: NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy.
abstract: N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteasome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson's disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation likely limits the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function.
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA. Electronic address: okaycaglayan@yahoo.com.
authors.forename: Ahmet Okay
authors.initials: AO
authors.lastname: Caglayan
authors.affiliation: Department of Pediatrics, Division of Pediatric Neurology, Sisli, Memorial Hospital, Istanbul 34385, Turkey.
authors.forename: Sinan
authors.initials: S
authors.lastname: Comu
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Baranoski
authors.affiliation: Department of Neurology, Istanbul University, Faculty of Medicine, Istanbul 34098, Turkey.
authors.forename: Yesim
authors.initials: Y
authors.lastname: Parman
authors.affiliation: Department of Genetics and Bioinformatics, Faculty of Engineering, Bahcesehir University, Istanbul 34353, Turkey.
authors.forename: Hande
authors.initials: H
authors.lastname: Kaymakçalan
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Gozde Tugce
authors.initials: GT
authors.lastname: Akgumus
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Caner
authors.initials: C
authors.lastname: Caglar
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Duygu
authors.initials: D
authors.lastname: Dolen
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Emine Zeynep
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Akdes Serin
authors.initials: AS
authors.lastname: Harmanci
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Ketu
authors.initials: K
authors.lastname: Mishra-Gorur
authors.affiliation: Genetic Disease Program, Sanford-Burnham Medical Research Institute, La Jolla 92037, CA, USA.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Neurogenetics, Yale School of Medicine, New Haven 06510, CT, USA. Electronic address: murat.gunel@yale.edu.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D002648:Child; D003318:Corneal Opacity / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009069:Movement Disorders / Q000235:genetics*; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000235:genetics*
chemical_list: D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
keywords: Deglycosylation; Intellectual disability; NGLY1; Neuromotor defect; Whole-exome sequencing