title: Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin-Bound Cobalamin and Mutations in ZNF143, Which Codes for a Transcriptional Activator.
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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Pupavac
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Petrella
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Janer
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Warren
authors.initials: W
authors.lastname: Cheung
authors.affiliation: Lunenfeld-Tanenbaum Research Institute at Sinai Health System and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Muenzer
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010088:Oxidoreductases; D010375:Pedigree; D015534:Trans-Activators / Q000235:genetics*; D014155:Transcobalamins / Q000378:metabolism*; D014805:Vitamin B 12 / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D015534:Trans-Activators; D014155:Transcobalamins; C114253:ZNF143 protein, human; C508359:MMACHC protein, human; D010088:Oxidoreductases; D014805:Vitamin B 12
keywords: ZNF143; cobalamin metabolism; inborn errors; transcobalamin; vitamin B12