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, gulliverm208 (gulm208). The notochord defect in gulm208 mutants is exacerbated under conditions of copper depletion or lysyl oxidase cuproenzyme inhibition that are without a notochord effect on wild-type embryos. The gulm208 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 gulm208 mutants. Of interest, the amino acid mutated in gulm208 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. Developmental Dynamics 237:3715–3726, 2008. © 2008 Wiley-Liss, Inc.