GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation
| Autor: | Thorsten Marquardt, Braulio Martínez, Otmar Huber, J. Christopher Hennings, Patricia Franzka, José M. Morales, Julia von Maltzahn, Susann Groth, Joachim Weis, M. Juliane Jung, Osvaldo M. Mutchinick, Christoph Kaether, Christian A. Hübner, Takfarinas Kentache, Istvan Katona, Rüdiger Horstkorte, Alessandro Ori, Svenja C. Schüler, Tanja Herrmann, Lutz Liebmann, Sonnhild Mittag, Lennart Gresing, Henriette Henze, Karina Biskup, Véronique Blanchard, Antje-Kathrin Huebner |
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| Přispěvatelé: | UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Guanosine Diphosphate Mannose Glycosylation Mannose Biology Alacrima Extracellular matrix 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine medicine Animals Humans Dystroglycans Muscle Skeletal Mice Knockout Skeletal muscle Muscle weakness General Medicine Neuromuscular Diseases medicine.disease Nucleotidyltransferases Cell biology 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Muscle Biology Neuron medicine.symptom Congenital disorder of glycosylation Research Article Genetic diseases |
| Zdroj: | The Journal of clinical investigation, Vol. 131, no.9, p. e139076 [1-19] (2021) J Clin Invest |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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