期刊
NATURE GENETICS
卷 41, 期 2, 页码 234-239出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.294
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资金
- University of Munster Medical School
- Centre National de la Recherche Scientifique
- Institut national de la sante et de la recherche medicale
- Agence Nationale de la Recherche
- Fonds de la Recherche en Sante du Quebec
- Canadian Institutes of Health Research
- Swiss National Foundation
- German Federal Ministry of Education and Research through the National Genome Research Network
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(1). In the cblF inborn error of vitamin B-12 metabolism, free vitamin accumulates in lysosomes, thus hindering its conversion to cofactors(2,3). 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.
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