2. Academic Validation
  3. Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function

  • Brain. 2020 Apr 1;143(4):1114-1126. doi: 10.1093/brain/awaa063.
Monica Zilmer 1,  Andrew C Edmondson 2 3,  Sumeet A Khetarpal 4,  Viola Alesi 5,  Maha S Zaki 6,  Kevin Rostasy 7,  Camilla G Madsen 8,  Francesca R Lepri 5,  Lorenzo Sinibaldi 5,  Raffaella Cusmai 9,  Antonio Novelli 5,  Mahmoud Y Issa 6,  Christina D Fenger 10 11,  Rami Abou Jamra 12,  Heiko Reutter 13 14,  Silvana Briuglia 15,  Emanuele Agolini 5,  Lars Hansen 16,  Ulla E Petäjä-Repo 17,  John Hintze 16,  Kimiyo M Raymond 18,  Kristen Liedtke 18,  Valentina Stanley 19,  Damir Musaev 19,  Joseph G Gleeson 19,  Cecilia Vitali 4,  W Timothy O'Brien 20,  Elena Gardella 21,  Guido Rubboli 10 22,  Daniel J Rader 2 3 4,  Katrine T Schjoldager 16,  Rikke S Møller 10 23
Affiliations

Affiliations

  • 1 Department of Paediatrics, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark.
  • 2 Department of Pediatrics, Division of Human Genetics, Section of Biochemical Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 3 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Medical Genetics Department, Bambino Gesù Children's Hospital, 00146 Rome, Italy.
  • 6 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 7 Department of Paediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, 45711 Datteln, Germany.
  • 8 Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, 2650 Hvidovre, Denmark.
  • 9 Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, 00146 Rome, Italy.
  • 10 Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark.
  • 11 Amplexa Genetics A/S, 5000 Odense C, Denmark.
  • 12 Institute of Human Genetics, University of Leipzig, 04103 Leipzig, Germany.
  • 13 Department of Neonatology and Pediatric Intensive Care, University Hospital of Bonn, 53012 Bonn, Germany.
  • 14 Institute of Human Genetics, University Hospital of Bonn, 53012 Bonn, Germany.
  • 15 Medical Genetics of Messina University, 98125 Messina, Italy.
  • 16 Copenhagen Centre for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
  • 17 Research Unit of Biomedicine, University of Oulu, 90014 University of Oulu, Finland.
  • 18 Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • 19 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, CA 92093, USA.
  • 20 Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 21 Department of Neurophysiology, Danish Epilepsy Centre Filadelfia, 4293 Dianalund, Denmark.
  • 22 Institute of Clinical Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
  • 23 Institute for Regional Health Services, University of Southern Denmark, 5000 Odense C, Denmark.
PMID: 32293671 DOI: 10.1093/brain/awaa063
Abstract

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of Apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein Cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

Keywords

O-glycosylation; GALNT2; HDL-cholesterol; apolipoprotein C-III glycosylation; congenital disorders of glycosylation.

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