Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism

Frank Rutsch; Susann Gailus; Isabelle R Miousse; Terttu Suormala; Corinne Sagné; Mohammad Reza Toliat; Gudrun Nürnberg; Tanja Wittkampf; Insa Buers; Azita Sharifi; Martin Stucki; Christian Becker; Matthias Baumgartner; Horst Robenek; Thorsten Marquardt; Wolfgang Höhne; Bruno Gasnier; David S Rosenblatt; Brian Fowler; Peter Nürnberg

doi:10.1038/ng.294

Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism

Nat Genet. 2009 Feb;41(2):234-9. doi: 10.1038/ng.294. Epub 2009 Jan 11.

Affiliation

¹ Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. rutschf@mednet.uni-muenster.de

PMID: 19136951
DOI: 10.1038/ng.294

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Child
Chromosome Deletion
Chromosome Mapping
Chromosomes, Human, Pair 6
Female
HeLa Cells
Humans
Hyperhomocysteinemia / complications*
Hyperhomocysteinemia / genetics
Lysosomal Membrane Proteins / metabolism
Male
Membrane Transport Proteins / deficiency*
Membrane Transport Proteins / genetics
Membrane Transport Proteins / metabolism
Methylmalonic Acid / metabolism*
Methylmalonic Acid / urine
Nucleocytoplasmic Transport Proteins / genetics
Nucleocytoplasmic Transport Proteins / metabolism
Nucleocytoplasmic Transport Proteins / physiology
Polymorphism, Genetic
Proteins / genetics*
Proteins / isolation & purification
Proteins / metabolism
Tissue Distribution
Transcobalamins / genetics*
Transcobalamins / isolation & purification
Transcobalamins / metabolism
Vitamin B 12 / metabolism*
Vitamin B 12 Deficiency / etiology
Vitamin B 12 Deficiency / genetics*
Vitamin B 12 Deficiency / metabolism

Substances

LAMP1 protein, human
LMBRD1 protein, human
Lysosomal Membrane Proteins
Membrane Transport Proteins
Nucleocytoplasmic Transport Proteins
Proteins
Transcobalamins
lysosomal proteins
Methylmalonic Acid
Vitamin B 12

Associated data

RefSeq/NP_060583
RefSeq/NP_071903