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

Authors
  • Pupavac, Mihaela1
  • Watkins, David1
  • Petrella, Francis1
  • Fahiminiya, Somayyeh1, 2
  • Janer, Alexandre3
  • Cheung, Warren2
  • Gingras, Anne-Claude4
  • Pastinen, Tomi1, 2
  • Muenzer, Joseph5
  • Majewski, Jacek1, 2
  • Shoubridge, Eric A3
  • Rosenblatt, David S1
  • 1 Department of Human Genetics, McGill University, Montreal, Quebec, Canada. , (Canada)
  • 2 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. , (Canada)
  • 3 Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, Quebec, Canada. , (Canada)
  • 4 Lunenfeld-Tanenbaum Research Institute at Sinai Health System and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. , (Canada)
  • 5 University of North Carolina, Chapel Hill, North Carolina, USA.
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Sep 01, 2016
Volume
37
Issue
9
Pages
976–982
Identifiers
DOI: 10.1002/humu.23037
PMID: 27349184
Source
Medline
Keywords
License
Unknown

Abstract

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.

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