GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation
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
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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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 2

Altered brain development and progressive neuron loss in Gmppa-KO mice.

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Altered brain development and progressive neuron loss in Gmppa-KO mice. ...
(A) Cortical layering is altered in Gmppa-KO mice. Sagittal sections of the somatosensory cortex of 3- and 12-month-old WT and KO mice were stained for the neuronal marker NeuN and neurons counted layer-wise (n = 4–6 mice per group; 2-way ANOVA with Bonferroni post hoc test). Scale bars: 50 μm. (B) Progressive loss of pyramidal neurons in the hippocampus of Gmppa-KO mice. Hippocampal sections of 3- and 12-month-old WT and KO mice were stained for NeuN and neurons counted in the CA1, CA2, and CA3 region of the hippocampus (n = 3–6 mice per group; 2-way ANOVA with Bonferroni post hoc test). Scale bars: 125 μm. (C) Progressive loss of Purkinje cells in Gmppa-KO mice. Cerebellar sections from 3- and 12-month-old WT and KO mice were stained for calbindin and Purkinje cells counted (n = 3–4 mice per group; 2-way ANOVA with Bonferroni post hoc test). Scale bars: 75 μm. (D) No obvious morphological changes of sciatic nerves of 12-month-old Gmppa-KO mice. Toluidine-blue stained semi-thin cross-sections of sciatic nerves of 12-month-old WT and KO mice. Total axon numbers and the distribution of axons of different diameters were analyzed (n = 3 mice per group; unpaired 2-tailed Student’s t test for axon number and 1-way ANOVA with Bonferroni post hoc test for distribution). Scale bars: 5 μm. (E) Amplitudes of distal compound muscle action potentials upon stimulation at the tail root and motor nerve conduction velocities were not changed in 12-month-old KO mice (n = 10 per group; 1-way ANOVA with Bonferroni post hoc test). (F) Sensory amplitudes upon stimulation at the tip of the tail were not changed in 12-month-old KO mice (n = 10 per group; 1-way ANOVA with Bonferroni post hoc test); sensory nerve conduction velocities were slightly decreased. Quantitative data are presented as mean ± SEM with individual data points.*P < 0.05; **P < 0.005; ***P < 0.0005.