title: Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism.
abstract: 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.
authors.affiliation: Division of Metabolism, Children's Research Center (CRC), University Children's Hospital, Zürich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Coelho
authors.forename: Jaeseung C
authors.initials: JC
authors.lastname: Kim
authors.forename: Isabelle R
authors.initials: IR
authors.lastname: Miousse
authors.forename: Stephen
authors.initials: S
authors.lastname: Fung
authors.forename: Marcel
authors.initials: M
authors.lastname: du Moulin
authors.forename: Insa
authors.initials: I
authors.lastname: Buers
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.forename: Patricie
authors.initials: P
authors.lastname: Burda
authors.forename: Michele
authors.initials: M
authors.lastname: Frapolli
authors.forename: Martin
authors.initials: M
authors.lastname: Stucki
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Horst
authors.initials: H
authors.lastname: Robenek
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.forename: Marzia
authors.initials: M
authors.lastname: Pasquali
authors.forename: Eugen
authors.initials: E
authors.lastname: Mengel
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006801:Humans; D007231:Infant, Newborn; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014805:Vitamin B 12 / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D018528:ATP-Binding Cassette Transporters; D051907:Lysosomal Membrane Proteins; D029543:Nucleocytoplasmic Transport Proteins; D014805:Vitamin B 12; C489273:ABCD4 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C502888:LMBRD1 protein, human