1. Academic Validation
  2. Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder

Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder

  • Am J Hum Genet. 2021 Jun 3;108(6):1151-1160. doi: 10.1016/j.ajhg.2021.04.017.
Eva Morava 1 Ulrich A Schatz 2 Pernille M Torring 3 Mary-Alice Abbott 4 Matthias Baumann 5 Charlotte Brasch-Andersen 6 Nathalie Chevalier 7 Ulrike Dunkhase-Heinl 8 Martin Fleger 9 Tobias B Haack 10 Stephen Nelson 11 Sven Potelle 7 Silvia Radenkovic 12 Guido T Bommer 7 Emile Van Schaftingen 7 Maria Veiga-da-Cunha 13
Affiliations

Affiliations

  • 1 Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
  • 2 Institute of Human Genetics, Department of Genetics and Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 3 Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
  • 4 Medical Genetics, Department of Pediatrics, University of Massachusetts Medical School - Baystate, Springfield, MA 01199, USA.
  • 5 Department of Pediatrics I, Division of Pediatric Neurology, Medical University Innsbruck, 6020 Innsbruck, Austria.
  • 6 Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark; Human Genetics, Faculty of Health, University of Southern Denmark, 5000 Odense, Denmark.
  • 7 de Duve Institute, UCLouvain, 1200 Brussels, Belgium.
  • 8 Department of Pediatrics, Hospital of Southern Jutland, 6200 Aabenraa, Denmark.
  • 9 Department of Pediatrics, Landeskrankenhaus Bregenz, 6900 Bregenz, Austria.
  • 10 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tübingen, 72076 Tübingen, Germany.
  • 11 Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA.
  • 12 Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Metabolomics Expertise Center, VIB-KU Leuven, 3000 Leuven, Belgium.
  • 13 de Duve Institute, UCLouvain, 1200 Brussels, Belgium. Electronic address: maria.veiga@uclouvain.be.
Abstract

We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases. These Enzymes form the hexose-1-phosphates crucial for NDP-sugars synthesis and ensuing glycosylation reactions. While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there. Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome Sequencing. All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and Other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally. Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect, but the clinical features observed in this neurodevelopmental disorder point toward an important but still unknown role of glucose-1,6-bisphosphate or Other sugar bisphosphates in brain metabolism.

Keywords

IMP; PMM1; brain development; congenital disorders of glycosylation; glucose-1,6-bisphosphatase; glucose-1,6-bisphosphate synthase; phosphoglucomutase.

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