| First Author | Franzka P | Year | 2021 |
| Journal | J Clin Invest | Volume | 131 |
| Issue | 9 | PubMed ID | 33755596 |
| Mgi Jnum | J:305791 | Mgi Id | MGI:6709824 |
| Doi | 10.1172/JCI139076 | Citation | Franzka P, et al. (2021) GMPPA defects cause a neuromuscular disorder with alpha-dystroglycan hyperglycosylation. J Clin Invest 131(9) |
| abstractText | 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 alpha-dystroglycan (alpha-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 alpha-DG in mice and humans. This increased alpha-DG turnover and thereby lowered alpha-DG abundance. In mice, dietary mannose restriction beginning after weaning corrected alpha-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 alpha-DG hyperglycosylation, to our knowledge, and we have unraveled underlying disease mechanisms and identified potential dietary treatment options. |
