GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• GDP-mannose-pyrophosphorylase-B (GMPPB) is crucial for glycosylation.
• GMPPB defects cause muscle disease via hypoglycosylation of α-dystroglycan (α-DG).
• Mutations in the related GMPPA cause AAMR syndrome, including muscle weakness.

Purpose of the Study:

• To investigate the role of GMPPA in AAMR syndrome.
• To elucidate the mechanism linking GMPPA defects to disease phenotypes.
• To identify potential therapeutic strategies for GMPPA-related disorders.

Main Methods:

• Generation and analysis of Gmppa-knockout (KO) mice.
• Biochemical assays to assess GDP-mannose levels and enzyme inhibition.
• Histological examination of muscle and brain tissues.
• Evaluation of cognitive and motor functions in mice.
• Dietary intervention with mannose restriction.

Main Results:

• Gmppa-KO mice exhibited cognitive and motor deficits, cortical layering defects, neuron loss, and myopathic changes.
• GMPPA acts as an allosteric feedback inhibitor of GMPPB, and its disruption leads to α-DG hyperglycosylation.
• Dietary mannose restriction in mice partially corrected α-DG glycosylation and abundance, improved muscle morphology, and prevented neuron degeneration and motor deficits.
• Cognitive performance and cortical layering were not improved by dietary intervention.

Conclusions:

• GMPPA defects represent a novel congenital disorder of glycosylation characterized by α-DG hyperglycosylation.
• GMPPA's inhibitory role in GDP-mannose synthesis is key to disease pathogenesis.
• Dietary mannose restriction shows potential as a therapeutic approach for certain aspects of GMPPA-related disorders.