Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism

Nat Genet. 2012 Oct;44(10):1152-5. doi: 10.1038/ng.2386. Epub 2012 Aug 26.


Inherited disorders of vitamin B12 (cobalamin) have provided important clues to how this vitamin, which is essential for hematological and neurological function, is transported and metabolized. We describe a new disease that results in failure to release vitamin B12 from lysosomes, which mimics the cblF defect caused by LMBRD1 mutations. Using microcell-mediated chromosome transfer and exome sequencing, we identified causal mutations in ABCD4, a gene that codes for an ABC transporter, which was previously thought to have peroxisomal localization and function. Our results show that ABCD4 colocalizes with the lysosomal proteins LAMP1 and LMBD1, the latter of which is deficient in the cblF defect. Furthermore, we show that mutations altering the putative ATPase domain of ABCD4 affect its function, suggesting that the ATPase activity of ABCD4 may be involved in intracellular processing of vitamin B12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism
  • Abnormalities, Multiple / enzymology
  • Abnormalities, Multiple / genetics*
  • Case-Control Studies
  • Cells, Cultured
  • DNA Mutational Analysis
  • Fibroblasts / metabolism
  • Gene Expression
  • Genes, Recessive
  • Genetic Association Studies
  • Humans
  • Infant, Newborn
  • Lysosomal Membrane Proteins / metabolism
  • Metabolism, Inborn Errors / enzymology
  • Metabolism, Inborn Errors / genetics*
  • Mutation*
  • Nucleocytoplasmic Transport Proteins / metabolism
  • Protein Structure, Tertiary
  • Protein Transport
  • Vitamin B 12 / metabolism*


  • ABCD4 protein, human
  • ATP-Binding Cassette Transporters
  • LAMP1 protein, human
  • LMBRD1 protein, human
  • Lysosomal Membrane Proteins
  • Nucleocytoplasmic Transport Proteins
  • Vitamin B 12