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Essential role for the alpha 1 chain of type VIII collagen in zebrafish notochord formation.

http://www.ncbi.nlm.nih.gov/pubmed/19035365

Several zebrafish mutants identified in large-scale forward genetic screens exhibit notochord distortion. We now report the cloning and further characterization of one such mutant, gulliver(m208) (gul(m208)). The notochord defect in gul(m208) mutants is exacerbated under conditions of copper depletion or lysyl oxidase cuproenzyme inhibition that are without a notochord effect on wild-type embryos. The gul(m208) phenotype results from a missense mutation in the gene encoding Col8a1, a lysyl oxidase substrate, and morpholino knockdown of col8a1 recapitulates the notochord distortion observed in gul(m208) mutants. Of interest, the amino acid mutated in gul(m208) Col8a1 is highly conserved, and the equivalent substitution in a closely related human protein, COL10A1, causes Schmid metaphyseal chondrodysplasia. Taken together, the data identify a new protein essential for notochord morphogenesis, extend our understanding of gene-nutrient interactions in early development, and suggest that human mutations in COL8A1 may cause structural birth defects.

Pubmed ID: 19035365 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Animals, Genetically Modified | Base Sequence | Collagen Type VIII | Conserved Sequence | Embryo, Nonmammalian | Gene Expression Regulation, Developmental | Microscopy, Electron, Transmission | Molecular Sequence Data | Mutation | Notochord | Phenotype | Protein Folding | Protein-Lysine 6-Oxidase | Sequence Alignment | Zebrafish

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK44464
  • Agency: NIDDK NIH HHS, Id: R01 DK044464
  • Agency: NIDDK NIH HHS, Id: R01 DK044464-13
  • Agency: NIDDK NIH HHS, Id: R01 DK061763
  • Agency: NIDDK NIH HHS, Id: R01 DK061763-11
  • Agency: NIGMS NIH HHS, Id: T32 GM07200

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