2. Academic Validation
  3. Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

  • Am J Hum Genet. 2021 Jul 1;108(7):1342-1349. doi: 10.1016/j.ajhg.2021.05.010.
Daniel L Polla 1,  Andrew C Edmondson 2,  Sandrine Duvet 3,  Michael E March 4,  Ana Berta Sousa 5,  Anna Lehman 6,  CAUSES Study,  Dmitriy Niyazov 7,  Fleur van Dijk 8,  Serwet Demirdas 9,  Marjon A van Slegtenhorst 9,  Anneke J A Kievit 9,  Celine Schulz 3,  Linlea Armstrong 6,  Xin Bi 10,  Daniel J Rader 11,  Kosuke Izumi 2,  Elaine H Zackai 2,  Elisa de Franco 12,  Paula Jorge 13,  Sophie C Huffels 14,  Marina Hommersom 14,  Sian Ellard 15,  Dirk J Lefeber 16,  Avni Santani 17,  Nicholas J Hand 18,  Hans van Bokhoven 14,  Miao He 19,  Arjan P M de Brouwer 20
Affiliations

Affiliations

  • 1 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
  • 2 Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 3 Université de Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
  • 4 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 5 Serviço de Genética Médica, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, 649-035 Lisboa, Portugal; Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal.
  • 6 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 7 Tulane School of Medicine, University of Queensland, 1315 Jefferson Highway, New Orleans, LA 70121, USA.
  • 8 North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Watford Road, Harrow, HA1 3UJ London, UK.
  • 9 Department of Clinical Genetics, Erasmus University Medical Center, 3015 Rotterdam, the Netherlands.
  • 10 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 11 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 12 Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, EX2 5DW Exeter, UK.
  • 13 Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, CHP, E.P.E., 4099-028 Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto, 4099-028 Porto, Portugal.
  • 14 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 15 Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, EX2 5DW Exeter, UK; College of Medicine and Health, University of Exeter, Barrack Road, EX2 5DW Exeter, UK.
  • 16 Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 17 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 18 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 19 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: hem@email.chop.edu.
  • 20 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: arjan.debrouwer@radboudumc.nl.
PMID: 34143952 DOI: 10.1016/j.ajhg.2021.05.010
Abstract

EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the Proteasome. In this study, through a combination of exome Sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.

Keywords

CDG; EDEM3; Mannosidase; N-glycan; UPR; dysmorphism; high-mannose; mouse.

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