The vitamin B12 processing enzyme, mmachc, is essential for zebrafish survival, growth and retinal morphology

Sloan, J.L., Achilly, N.P., Arnold, M.L., Catlett, J.L., Blake, T., Bishop, K., Jones, M., Harper, U., English, M.A., Anderson, S., Trivedi, N.S., Elkahloun, A., Hoffmann, V., Brooks, B.P., Sood, R., Venditti, C.P.
Human molecular genetics   29(13): 2109-2123 (Journal)
Registered Authors
Brooks, Brian P., English, Milton A., Sood, Raman
MeSH Terms
  • Animals
  • Carrier Proteins/genetics*
  • Homocystinuria/genetics
  • Homocystinuria/pathology
  • Humans
  • Mice
  • Morphogenesis/genetics*
  • Mutation/genetics
  • Optic Nerve/growth & development
  • Optic Nerve/pathology
  • Oxidoreductases/genetics
  • Retina/growth & development
  • Retina/metabolism
  • Vitamin B 12/analogs & derivatives
  • Vitamin B 12/genetics*
  • Vitamin B 12/metabolism
  • Vitamin B 12 Deficiency/genetics*
  • Vitamin B 12 Deficiency/metabolism
  • Vitamin B 12 Deficiency/pathology
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish Proteins/genetics*
32186706 Full text @ Hum. Mol. Genet.
Cobalamin C deficiency (cblC), the most common inborn error of intracellular cobalamin metabolism, is caused by mutations in MMACHC, a gene responsible for the processing and intracellular trafficking of vitamin B12. This recessive disorder is characterized by a failure to metabolize cobalamin into adenosyl- and methylcobalamin, which results in the biochemical perturbations of methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia caused by impaired activity of the downstream enzymes, methylmalonyl-CoA mutase and methionine synthase. Cobalamin C deficiency can be accompanied by a wide spectrum of clinical manifestations, including progressive blindness, and in mice, manifests with very early embryonic lethality. Because zebrafish harbor a full complement of cobalamin metabolic enzymes, we used genome editing to study loss of mmachc function and to develop the first viable animal model of cblC deficiency. Mmachc mutants survived the embryonic period but perished in early juvenile life. The mutants displayed metabolic and clinical features of cblC deficiency including methylmalonic acidemia, severe growth retardation, and lethality. Morphologic and metabolic parameters improved when the mutants were raised in water supplemented with small molecules used to treat patients, including hydroxocobalamin, methylcobalamin, methionine, and betaine. Furthermore, mmachc mutants bred to express rod and or cone fluorescent reporters, manifested a retinopathy and thin optic nerves. Expression analysis using whole eye mRNA revealed dysregulation of genes involved in phototransduction and cholesterol metabolism. Zebrafish with mmachc deficiency recapitulate the several of the phenotypic and biochemical features of the human disorder, including ocular pathology, and show a response to established treatments.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes