Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin-Bound Cobalamin and Mutations in ZNF143, Which Codes for a Transcriptional Activator

Hum Mutat. 2016 Sep;37(9):976-82. doi: 10.1002/humu.23037. Epub 2016 Jul 12.


Vitamin B12 (cobalamin, Cbl) cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) are required for the activity of the enzymes methylmalonyl-CoA mutase (MCM) and methionine synthase (MS). Inborn errors of Cbl metabolism are rare Mendelian disorders associated with hematological and neurological manifestations, and elevations of methylmalonic acid and/or homocysteine in the blood and urine. We describe a patient whose fibroblasts had decreased functional activity of MCM and MS and decreased synthesis of AdoCbl and MeCbl (3.4% and 1.0% of cellular Cbl, respectively). The defect in cultured patient fibroblasts complemented those from all known complementation groups. Patient cells accumulated transcobalamin-bound-Cbl, a complex which usually dissociates in the lysosome to release free Cbl. Whole-exome sequencing identified putative disease-causing variants c.851T>G (p.L284*) and c.1019C>T (p.T340I) in transcription factor ZNF143. Proximity biotinylation analysis confirmed the interaction between ZNF143 and HCFC1, a protein that regulates expression of the Cbl trafficking enzyme MMACHC. qRT-PCR analysis revealed low MMACHC expression levels both in patient fibroblasts, and in control fibroblasts incubated with ZNF143 siRNA.

Keywords: ZNF143; cobalamin metabolism; inborn errors; transcobalamin; vitamin B12.

MeSH terms

  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cytoplasm / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Infant
  • Male
  • Metabolism, Inborn Errors / genetics*
  • Metabolism, Inborn Errors / metabolism
  • Metabolism, Inborn Errors / pathology
  • Mutation
  • Oxidoreductases
  • Pedigree
  • Trans-Activators / genetics*
  • Transcobalamins / metabolism*
  • Vitamin B 12 / metabolism*


  • Carrier Proteins
  • Trans-Activators
  • Transcobalamins
  • ZNF143 protein, human
  • MMACHC protein, human
  • Oxidoreductases
  • Vitamin B 12