Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation
Patricia Franzka, … , Julia von Maltzahn, Christian A. Hübner
Patricia Franzka, … , Julia von Maltzahn, Christian A. Hübner
Published March 23, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI139076.
View: Text | PDF
Research In-Press Preview Muscle biology

GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation

  • Text
  • PDF
Abstract

GDP-mannose-pyrophosphorylase-B (GMPPB) facilitates the generation of GDP-mannose, a sugar donor required for glycosylation. GMPPB defects cause muscle disease due to hypoglycosylation of α-dystroglycan (α-DG). Alpha-DG is part of a protein complex, which links the extracellular matrix with the cytoskeleton thus stabilizing myofibers. Mutations of the catalytically inactive homolog GMPPA cause AAMR syndrome, which is characterized by achalasia, alacrima, mental retardation, and muscle weakness. Here we show that Gmppa KO mice recapitulate cognitive and motor deficits. As structural correlates we found cortical layering defects, progressive neuron loss, and myopathic alterations. Increased GDP-mannose levels in skeletal muscle and in vitro assays identify GMPPA as an allosteric feedback inhibitor of GMPPB. Thus, its disruption enhances mannose incorporation into glycoproteins including α-Dg in mice and men. This increases α-Dg turnover and thereby lowers α-Dg abundance. In mice dietary mannose restriction beginning after weaning corrects α-DG hyperglycosylation and abundance, normalizes skeletal muscle morphology, and prevents neuron degeneration and the development of motor deficits. Cortical layering and cognitive performance, however, are not improved. We thus identify GMPPA defects as the first congenital disorder of glycosylation characterized by α-DG hyperglycosylation, unravel underlying disease mechanisms and point to potential dietary treatment options.

Authors

Patricia Franzka, Henriette Henze, M. Juliane Jung, Svenja C. Schüler, Sonnhild Mittag, Karina Biskup, Lutz Liebmann, Takfarinas Kentache, José Morales, Braulio Martínez, Istvan Katona, Tanja Herrmann, Antje-Kathrin Huebner, J. Christopher Hennings, Susann Groth, Lennart J. Gresing, Rüdiger Horstkorte, Thorsten Marquardt, Joachim Weis, Christoph Kaether, Osvaldo M. Mutchinick, Alessandro Ori, Otmar Huber, Véronique Blanchard, Julia von Maltzahn, Christian A. Hübner

×

Full Text PDF | Download (2.57 MB)


Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts