ArticleThe Journal of clinical investigation2021
GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Gmppb-mutant mice exhibit dystroglycanopathy symptoms that are rescued with GSK3β inhibition or AAV-mediated GMPPB gene replacement.Nature communications · 2026Article
- Proteomic compensation by paralogs preserves protein interaction networks after gene loss in cancer.Molecular systems biology · 2025Article
- Achalasia and mental retardation in a child with uniparental disomy ofGastroenterology report · 2025Article
- Evolutionary rate covariation is pervasive between glycosylation pathways and points to potential disease modifiers.PLoS genetics · 2024Article
- Molecular mechanisms and therapeutic strategies for neuromuscular diseases.Cellular and molecular life sciences : CMLS · 2024Review
- Investigating the shared genetic architecture of osteoarthritis and frailty: a genome-wide cross-trait analysis.American journal of nuclear medicine and molecular imaging · 2024Article
- Consequences of GMPPB deficiency for neuromuscular development and maintenance.Frontiers in molecular neuroscience · 2024Article
- Ubiquitination contributes to the regulation of GDP-mannose pyrophosphorylase B activity.Frontiers in molecular neuroscience · 2024Article
- Article
- Impact of Hypermannosylation on the Structure and Functionality of the ER and the Golgi Complex.Biomedicines · 2023Article
- Hypolacrimia and Alacrimia as Diagnostic Features for Genetic or Congenital Conditions.Investigative ophthalmology & visual science · 2022Review
- A rare cause of infantile achalasia: GMPPA-congenital disorder of glycosylation with two novel compound heterozygous variants.American journal of medical genetics. Part A · 2022Article
- Genetic pain loss disorders.Nature reviews. Disease primers · 2022Review
- Altered mannose metabolism in chronic stress and depression is rapidly reversed by vitamin B12.Frontiers in nutrition · 2022Article
- Altered Glycosylation in the Aging Heart.Frontiers in molecular biosciences · 2021Article
- Phenotypic and genotypic description of GMPPA-congenital disorder of glycosylation: A review of 26 cases.Molecular genetics and metabolismArticle
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Authors and funding
26 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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