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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


  • Cline A
  • Gao N
  • Flanagan-Steet H
  • Sharma V
  • Rosa S
  • Sonon R
  • Azadi P
  • Sadler KC
  • Freeze HH
  • Lehrman MA
  • Steet R


Molecular biology of the cell

Publication Data

November 31, 2012

Associated Grants

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

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