title: Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.
abstract: OBJECTIVE
  The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.
  
  
  METHODS
  Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.
  
  
  RESULTS
  All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.
  
  
  CONCLUSIONS
  NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bainbridge
authors.affiliation: Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Farah R
authors.initials: FR
authors.lastname: Zahir
authors.affiliation: Epilepsy Centre Kork, Kehl, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bast
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Crimian
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Schoch
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Platt
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cox
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
authors.forename: Mena
authors.initials: M
authors.lastname: Scavina
authors.affiliation: Division of Developmental Medicine, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
authors.forename: Rhonda S
authors.initials: RS
authors.lastname: Walter
authors.affiliation: Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bibb
authors.affiliation: Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Jones
authors.affiliation: Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Hegde
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Medicine, Imperial College, London, UK.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Need
authors.affiliation: Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Angelica
authors.initials: A
authors.lastname: Oviedo
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Schaaf
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Boyle
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clark
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Rajini
authors.initials: R
authors.lastname: Haraksingh
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Cowan
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Langlois
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA [3] Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: 1] Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA [2] Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000473:pathology; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000473:pathology; D009069:Movement Disorders / Q000473:pathology; D009123:Muscle Hypotonia / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000172:deficiency / Q000235:genetics*; D012189:Retrospective Studies; D012640:Seizures / Q000473:pathology; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction / Q000235:genetics*; D055815:Young Adult
chemical_list: D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase