title: Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism.
abstract: Vitamin B(12) (cobalamin) is essential in animals for metabolism of branched chain amino acids and odd chain fatty acids, and for remethylation of homocysteine to methionine. In the cblF inborn error of vitamin B(12) metabolism, free vitamin accumulates in lysosomes, thus hindering its conversion to cofactors. Using homozygosity mapping in 12 unrelated cblF individuals and microcell-mediated chromosome transfer, we identified a candidate gene on chromosome 6q13, LMBRD1, encoding LMBD1, a lysosomal membrane protein with homology to lipocalin membrane receptor LIMR. We identified five different frameshift mutations in LMBRD1 resulting in loss of LMBD1 function, with 18 of the 24 disease chromosomes carrying the same mutation embedded in a common 1.34-Mb haplotype. Transfection of fibroblasts of individuals with cblF with wild-type LMBD1 rescued cobalamin coenzyme synthesis and function. This work identifies LMBRD1 as the gene underlying the cblF defect of cobalamin metabolism and suggests that LMBD1 is a lysosomal membrane exporter for cobalamin.
authors.affiliation: Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. rutschf@mednet.uni-muenster.de
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.forename: Susann
authors.initials: S
authors.lastname: Gailus
authors.forename: Isabelle R
authors.initials: IR
authors.lastname: Miousse
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.forename: Corinne
authors.initials: C
authors.lastname: Sagné
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Toliat
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Tanja
authors.initials: T
authors.lastname: Wittkampf
authors.forename: Insa
authors.initials: I
authors.lastname: Buers
authors.forename: Azita
authors.initials: A
authors.lastname: Sharifi
authors.forename: Martin
authors.initials: M
authors.lastname: Stucki
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumgartner
authors.forename: Horst
authors.initials: H
authors.lastname: Robenek
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.forename: Bruno
authors.initials: B
authors.lastname: Gasnier
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
mesh_terms: D002648:Child; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000235:genetics; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008764:Methylmalonic Acid / Q000378:metabolism* / Q000652:urine; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D014018:Tissue Distribution; D014155:Transcobalamins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051907:Lysosomal Membrane Proteins; D026901:Membrane Transport Proteins; D008764:Methylmalonic Acid; D029543:Nucleocytoplasmic Transport Proteins; D011506:Proteins; D014155:Transcobalamins; D014805:Vitamin B 12; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C502888:LMBRD1 protein, human; C018589:lysosomal proteins