Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type

Nat Genet. 2006 Jan;38(1):93-100. doi: 10.1038/ng1683. Epub 2005 Nov 27.


Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line
  • Chromosome Mapping
  • Conserved Sequence
  • Fibroblasts / metabolism
  • Haplotypes / genetics
  • Homocystinuria / genetics*
  • Humans
  • Membrane Proteins / chemistry
  • Metabolism, Inborn Errors / genetics*
  • Methylmalonic Acid / urine*
  • Molecular Sequence Data
  • Mutation*
  • Oxidoreductases
  • Protein Folding
  • Structural Homology, Protein
  • Vitamin B 12 / metabolism


  • Bacterial Proteins
  • Carrier Proteins
  • Membrane Proteins
  • tonB protein, Bacteria
  • Methylmalonic Acid
  • MMACHC protein, human
  • Oxidoreductases
  • Vitamin B 12

Associated data

  • OMIM/277400
  • PDB/1XX3