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 1

Gmppa-KO mice show progressive motor deficits and cognitive impairments.

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Gmppa-KO mice show progressive motor deficits and cognitive impairments...
(A) Genomic structure of the WT and targeted Gmppa locus. Gray rectangles: exons; black rectangles: Frt sites; black triangles: loxP sites; LacZ: β-galactosidase cassette; NeomR: neomycin-resistance cassette. Black lines: probe-binding sites. (B) The GMPPA protein was detected in different tissues of WT mice, but was absent in KO samples. GMPPB abundance was not altered in Gmppa-KO mice. GAPDH served as loading control. (C) The foot-base angle (FBA) flattened in KO mice (n = 12 mice per group; 2-way ANOVA with Bonferroni post hoc test). (D) KO mice could hold less weight with their forepaws (n = 12 mice per group; 2-way ANOVA with Bonferroni post hoc test). (E) Aged KO mice fell off earlier from an inverted screen (n = 12 mice per group; 2-way ANOVA with Bonferroni post hoc test). (F) Cued and contextual fear conditioning test in 3- and 12-month-old WT and KO mice. Freezing behavior during the test was measured as an index of fear memory. For acquisition, mice were placed into a conditioning chamber and were given pairings of a tone and an electric foot-shock. After 24 hours, mice were either exposed to a different chamber with presentation of the auditory cue (cued test) or the same context as for acquisition (context test). Although both genotypes remembered the conditioned stimulus, KO mice were unable to remember the context of the aversive stimulus (n = 12 mice per group; 2-way ANOVA with Bonferroni post hoc test). Quantitative data are presented as mean ± SEM with individual data points. ***P < 0.0005.