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;131(9):e139076. https://doi.org/10.1172/JCI139076.
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Research Article Muscle biology

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.

Authors

Patricia Franzka, Henriette Henze, M. Juliane Jung, Svenja Caren 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 Gresing, Rüdiger Horstkorte, Thorsten Marquardt, Joachim Weis, Christoph Kaether, Osvaldo M. Mutchinick, Alessandro Ori, Otmar Huber, Véronique Blanchard, Julia von Maltzahn, Christian A. Hübner

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Figure 3

Gmppa-KO mice develop an age-dependent myopathy.

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Gmppa-KO mice develop an age-dependent myopathy. (A) Reduced muscle mas...
(A) Reduced muscle mass in 12-month-old KO mice (n = 5 males each; Student’s t test). (B) Decreased myofiber diameter and centralized nuclei in skeletal muscle sections of 12-month-old KO mice (n = 3 mice per group; unpaired 2-tailed Student’s t test). Scale bars: 50 μm. (C) Increased number of TUNEL-positive nuclei in KO mice (n = 5 mice per group; unpaired 2-tailed Student’s t test). (D) No relevant skeletal muscle fibrosis at 12 months of age as judged from Picro-Sirius red staining (n = 3 mice per group; unpaired 2-tailed Student’s t test). Scale bars: 200 μm. (E) Increased number of developmental myosin heavy chain (green) positive satellite cells in skeletal muscle of 12-month-old KO mice (n = 6 mice per group; unpaired 2-tailed Student’s t test). Scale bars: 50 μm. (F–H) Altered distribution of the ECM proteins laminin (F), nidogen (G), and collagen IV (H) in skeletal muscles of 12-month-old KO mice. Overviews and control staining with secondary antibodies alone are shown in Supplemental Figure 2. Scale bars: 5 μm. (I) Less compact and less tight connection of endomysial collagen to myofiber basal lamina in KO samples. Scale bars: 1 μm. (J) Mass spectrometry analysis of skeletal muscle proteins of 12-month-old WT and KO mice. Proteins significantly upregulated in KO are shown in red; those downregulated in blue (threshold q < 0.2; n = 5 mice per genotype). The red font refers to genes related to muscle contraction. (K) Irregular α-actinin pattern in skeletal muscle of 12-month-old KO mice (arrowheads). Scale bars: 10 μm; n = 3 mice per group. (L) Myofibrillar disintegration with Z-band streaming (arrows). Sarcomeres surrounding the lesion show a normal Z-band pattern. Scale bar: 2 μm. Quantitative data are presented as mean ± SEM with individual data points. *P < 0.05; ***P < 0.0005.