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A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency.

Congenital disorder of glycosylation (PMM2-CDG) results from mutations in pmm2, which encodes the phosphomannomutase (Pmm) that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P). Patients have wide-spectrum clinical abnormalities associated with impaired protein N-glycosylation. Although it has been widely proposed that Pmm2 deficiency depletes M1P, a precursor of GDP-mannose, and consequently suppresses lipid-linked oligosaccharide (LLO) levels needed for N-glycosylation, these deficiencies have not been demonstrated in patients or any animal model. Here we report a morpholino-based PMM2-CDG model in zebrafish. Morphant embryos had developmental abnormalities consistent with PMM2-CDG patients, including craniofacial defects and impaired motility associated with altered motor neurogenesis within the spinal cord. Significantly, global N-linked glycosylation and LLO levels were reduced in pmm2 morphants. Although M1P and GDP-mannose were below reliable detection/quantification limits, Pmm2 depletion unexpectedly caused accumulation of M6P, shown earlier to promote LLO cleavage in vitro. In pmm2 morphants, the free glycan by-products of LLO cleavage increased nearly twofold. Suppression of the M6P-synthesizing enzyme mannose phosphate isomerase within the pmm2 background normalized M6P levels and certain aspects of the craniofacial phenotype and abrogated pmm2-dependent LLO cleavage. In summary, we report the first zebrafish model of PMM2-CDG and uncover novel cellular insights not possible with other systems, including an M6P accumulation mechanism for underglycosylation.

Pubmed ID: 22956764 RIS Download

Mesh terms: Animals | Cartilage | Cell Shape | Chondrocytes | Congenital Disorders of Glycosylation | Craniofacial Abnormalities | Disease Models, Animal | Embryo, Nonmammalian | Gene Expression Regulation, Developmental | Glycosylation | Lipopolysaccharides | Mannose-6-Phosphate Isomerase | Mannosephosphates | Morpholinos | Motor Neurons | Movement | Neurogenesis | Phosphotransferases (Phosphomutases) | Skull | Spinal Cord | Substrate Specificity | Zebrafish | Zebrafish Proteins

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01-GM086524
  • Agency: NIGMS NIH HHS, Id: R01-GM038545
  • Agency: NIGMS NIH HHS, Id: R01 GM086524
  • Agency: NIGMS NIH HHS, Id: P41 GM103490
  • Agency: NIAAA NIH HHS, Id: R01 AA018886
  • Agency: NIGMS NIH HHS, Id: R01 GM038545
  • Agency: NIAAA NIH HHS, Id: R01-AA018886
  • Agency: NICHD NIH HHS, Id: RC1 HD064159

ZFIN (Data, Gene Expression)

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