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Mutations in NGLY1 Cause an Inherited Disorder of the Endoplasmic Reticulum–Associated Degradation Pathway

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Mutations in NGLY1 Cause an Inherited Disorder of the Endoplasmic Reticulum–Associated Degradation Pathway © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum–associated degradation pathway Gregory M. Enns, MB, ChB1, Vandana Shashi, MD, MBBS2, Matthew Bainbridge, PhD3, Michael J. Gambello, MD, PhD4, Farah R. Zahir, PhD5, Thomas Bast, MD6, Rebecca Crimian, MS2, Kelly Schoch, MS2, Julia Platt, MS1, Rachel Cox, MS1, Jonathan A. Bernstein, MD, PhD1, Mena Scavina, DO7, Rhonda S. Walter, MD8, Audrey Bibb, MS4, Melanie Jones, PhD4, Madhuri Hegde, PhD4, Brett H. Graham, MD, PhD3, Anna C. Need, PhD9, Angelica Oviedo, MD10, Christian P. Schaaf, MD, PhD3,11, Sean Boyle, PhD12, Atul J. Butte, MD, PhD12, Rong Chen, PhD12, Michael J. Clark, PhD12, Rajini Haraksingh, PhD12, Tina M. Cowan, PhD13, FORGE Canada Consortium, Ping He, MD, PhD14, Sylvie Langlois, MD5, Huda Y. Zoghbi, MD3,11,15, Michael Snyder, PhD12, Richard A. Gibbs, PhD3,16, Hudson H. Freeze, PhD14 and David B. Goldstein, PhD17,18 Purpose: The endoplasmic reticulum–associated degradation path- age material or vacuolization (5/6), and seizures (4/8). The nonsense way is responsible for the translocation of misfolded proteins across mutation c.1201A>T (p.R401X) was the most common deleterious the endoplasmic reticulum membrane into the cytosol for subsequent allele. degradation by the proteasome. To define the phenotype associated Conclusion: with a novel inherited disorder of cytosolic endoplasmic reticulum– NGLY1 deficiency is a novel autosomal recessive dis- associated degradation pathway dysfunction, we studied a series of order of the endoplasmic reticulum–associated degradation pathway eight patients with deficiency of N-glycanase 1. associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a Methods: Whole-genome, whole-exome, or standard Sanger specific nonsense mutation that appears to be associated with severe sequencing techniques were employed. Retrospective chart reviews disease. The phenotypic spectrum is likely to enlarge as cases with a were performed in order to obtain clinical data. broader range of mutations are detected. Results: All patients had global developmental delay, a movement Genet Med advance online publication 20 March 2014 disorder, and hypotonia. Other common findings included hypo- lacrima or alacrima (7/8), elevated liver transaminases (6/7), micro- Key Words: alacrima; choreoathetosis; liver disease; NGLY1; cephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic stor- ­seizures INTRODUCTION degradation (ERAD) machinery along with the AAA ATPase The enzyme N-glycanase 1 (NGLY1), also known as peptide:N- complex p97.10,11 The ERAD pathway is a mechanism for iden- glycanase (PNGase, EC 3.5.1.52), catalyzes protein deglycosyl- tifying and degrading misfolded glycoproteins. N-glycans that ation by cleaving the β-aspartyl glycosylamine bond of N-linked are high in mannose content act as quality control tags for pro- glycoproteins with the subsequent release of intact N-glycan teins in the early stages of the secretory pathway.12,13 Misfolded species.1 NGLY1 activity was first described in almond seeds1 glycoproteins are detected by ER luminal lectins and are then but is ubiquitously present across a wide range of species, translocated to the cytosol via the ERAD machinery to be sub- including bacteria,2 yeast,3–5 amoeba,6 fish,7 and mammals.8,9 sequently degraded by cytosolic enzymes including NGLY1.14 Evidence suggests that NGLY1 participates as a key cytoplas- To date, a single patient with NGLY1 deficiency has been mic component of the endoplasmic reticulum–associated reported as part of a whole-exome sequencing (WES) study The first three authors contributed equally to this study. 1Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children’s Hospital, Stanford University, Stanford, California, USA; 2Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA; 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; 4Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA; 5Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; 6Epilepsy Centre Kork, Kehl, Germany; 7Division of Pediatric Neurology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA; 8Division of Developmental Medicine, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA; 9Department of Medicine, Imperial College, London, UK; 10Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; 11Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, USA; 12Department of Genetics, Stanford University, Stanford, California, USA; 13Department of Pathology, Stanford University, Stanford, California, USA; 14Sanford-Burnham Medical Research Institute, La Jolla, California, USA; 15Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA; 16Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA; 17Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA; 18Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA. Correspondence: Gregory M. Enns ([email protected]) Submitted 30 December 2013; accepted 9 February 2014; advance online publication 20 March 2014. doi:10.1038/gim.2014.22 GENETICS in mEDICINE | Volume 16 | Number 10 | October 2014 751 ORIGINAL RESEARCH ARTICLE ENNS et al | Clinical and molecular features of N-glycanase 1 deficiency focusing on the utility of this technology to detect the underly- some variation in overall severity was observed, with the most ing genetic etiology of disorders affecting patients with previ- common mutation being associated with more severe out- ously undiagnosed or unresolved genetic conditions.15 Need et comes (Table 1). All patients had global developmental delay, al.15 described a 3-year-old boy with compound heterozygous a movement disorder, and hypotonia. Other common findings inactivating mutations in NGLY1 and suggested that this could included hypolacrima or alacrima (7/8), electroencephalogra- be a new disorder. The initial patient had a clinical phenotype phy (EEG) abnormalities (7/8), elevated liver transaminases suggestive of a congenital disorder of glycosylation (CDG), (6/7), microcephaly (6/8), abnormal brain imaging (6/8), although repeated transferrin isoelectric focusing and N-glycan diminished reflexes (6/8), hepatocyte cytoplasmic storage mate- analyses were normal. Liver biopsy showed accumulation of an rial or vacuolization (5/6), seizures (4/8), and abnormal nerve amorphous unidentified substance throughout the cytoplasm—a conduction (3/3) (Figure 1). Although all patients had cogni- finding likely consistent with NGLY1 dysfunction—which would tive, motor, and speech impairment, developmental regression be expected to result in abnormal accumulation of misfolded gly- was noted only in Patients 5 and 8. Patients did not have sig- coproteins because of impaired cytosolic degradation.15 We now nificant synthetic dysfunction or a coagulopathy, despite the report clinical and molecular findings present in seven newly elevations in liver transaminases. Two of the patients died pre- diagnosed patients with mutations in NGLY1, as well as further maturely, at 9 months and 5 years of age, respectively. Pedigrees details related to the original case. These observations confirm for all patients are shown in Figure 2. Short clinical summa- NGLY1 deficiency as an inherited disorder associated with the ries are provided below. Further details may be found in the ERAD process and document its clinical presentation. Supplementary Materials and Methods online. Patient 1, a now 5-year-old boy, presented in the neona- MATERIALS AND METHODS tal period with involuntary movements, including athetosis The Stanford Institutional Review Board approved this study. involving the trunk and extremities and constant lip smacking Clinical data were abstracted from the medical records by and pursing while awake. Global developmental delay; hypo- retrospective chart review. Further data were collected by tonia; intractable multifocal epilepsy, consisting of myoclonic direct interaction with the families of participating subjects. seizures, drop attacks, and staring or tonic episodes; and liver Ascertainment occurred by patient families, treating physi- disease were present in infancy. He has cortical vision impair- cians, or both directly contacting the primary or senior authors ment and congenital alacrima, and corneal ulcerations with following the publication of the original article describing a scarring were noted at the age of 4 years. Now, at 5 years of age, case of NGLY1 deficiency.15 An Internet blog started by the the movement disorder has not abated and he has central hypo- father of the initial patient was instrumental in connecting tonia and global developmental delay. NGLY1-deficient patient families with physicians and scientists Patient 2, a now 20-year-old female, was born at 39 weeks of studying this novel disorder (see accompanying Commentary gestation via Cesarean section because of intrauterine growth by
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