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GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation.

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 alacrima, achalasia, and mental retardation syndrome (AAMR syndrome), which also involves muscle weakness. Here, we showed that Gmppa-KO mice recapitulated 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 identified GMPPA as an allosteric feedback inhibitor of GMPPB. Thus, its disruption enhanced mannose incorporation into glycoproteins, including α-DG in mice and humans. This increased α-DG turnover and thereby lowered α-DG abundance. In mice, dietary mannose restriction beginning after weaning corrected α-DG hyperglycosylation and abundance, normalized skeletal muscle morphology, and prevented neuron degeneration and the development of motor deficits. Cortical layering and cognitive performance, however, were not improved. We thus identified GMPPA defects as the first congenital disorder of glycosylation characterized by α-DG hyperglycosylation, to our knowledge, and we have unraveled underlying disease mechanisms and identified potential dietary treatment options.

SUBMITTER: Franzka P

PROVIDER: S-EPMC8087212 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation.

Franzka Patricia P Henze Henriette H Jung M Juliane MJ Schüler Svenja Caren SC Mittag Sonnhild S Biskup Karina K Liebmann Lutz L Kentache Takfarinas T Morales José J Martínez Braulio B Katona Istvan I Herrmann Tanja T Huebner Antje-Kathrin AK Hennings J Christopher JC Groth Susann S Gresing Lennart L Horstkorte Rüdiger R Marquardt Thorsten T Weis Joachim J Kaether Christoph C Mutchinick Osvaldo M OM Ori Alessandro A Huber Otmar O Blanchard Véronique V von Maltzahn Julia J Hübner Christian A CA

The Journal of clinical investigation 20210501 9

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 alacrima, achalasia, and mental retardation syndrome (AAMR syndrome), which also involves muscle weakn ...[more]

PMID: 33755596

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Project description:BACKGROUND:LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of ?-dystroglycan. Overexpression of LARGE induces hyperglycosylation of ?-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored. METHODOLOGY/PRINCIPAL FINDINGS:In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with ?-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage. CONCLUSIONS/SIGNIFICANCE:This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and ?-dystroglycan hyperglycosylation in muscle should be safe.

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Dataset Information

GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation.

Publications

GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation.

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