Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism.
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.
Rutsch
Frank
F
Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany. rutschf@mednet.uni-muenster.de
Gailus
Susann
S
Miousse
Isabelle R
IR
Suormala
Terttu
T
Sagné
Corinne
C
Toliat
Mohammad Reza
MR
Nürnberg
Gudrun
G
Wittkampf
Tanja
T
Buers
Insa
I
Sharifi
Azita
A
Stucki
Martin
M
Becker
Christian
C
Baumgartner
Matthias
M
Robenek
Horst
H
Marquardt
Thorsten
T
Höhne
Wolfgang
W
Gasnier
Bruno
B
Rosenblatt
David S
DS
Fowler
Brian
B
Nürnberg
Peter
P
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
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