دورية أكاديمية
GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation.
| العنوان: | GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation. |
|---|---|
| المؤلفون: | Franzka, Patricia, Henze, Henriette, Jung, M Juliane, Schüler, Svenja Caren, Mittag, Sonnhild, Biskup, Karina, Liebmann, Lutz, Kentache, Takfarinas, Morales, José, MartÃnez, Braulio, Katona, Istvan, Herrmann, Tanja, Huebner, Antje-Kathrin, Hennings, J Christopher, Groth, Susann, Gresing, Lennart, Horstkorte, Rüdiger, Marquardt, Thorsten, Weis, Joachim, Kaether, Christoph, Mutchinick, Osvaldo M, Ori, Alessandro, Huber, Otmar, Blanchard, Véronique, von Maltzahn, Julia, Hübner, Christian A |
| المساهمون: | UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique |
| المصدر: | The Journal of clinical investigation, Vol. 131, no.9, p. e139076 [1-19] (2021) |
| بيانات النشر: | American Society for Clinical Investigation |
| سنة النشر: | 2021 |
| المجموعة: | DIAL@USL-B (Université Saint-Louis, Bruxelles) |
| مصطلحات موضوعية: | Animals, Dystroglycans, Glycosylation, Guanosine Diphosphate Mannose, Humans, Mice, Knockout, Muscle, Skeletal, Neuromuscular Diseases, Nucleotidyltransferases, Genetic diseases, Muscle Biology |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0021-9738 1558-8238 |
| العلاقة: | boreal:264486; http://hdl.handle.net/2078.1/264486Test; info:pmid/33755596; urn:ISSN:0021-9738; urn:EISSN:1558-8238 |
| DOI: | 10.1172/JCI139076 |
| الإتاحة: | https://doi.org/10.1172/JCI139076Test http://hdl.handle.net/2078.1/264486Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.69AD8F08 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00219738 15588238 |
|---|---|
| DOI: | 10.1172/JCI139076 |