Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism
Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism
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DOI：
10.1038/ng.294
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发表时间：
2009-02-01
期刊：
影响因子：
30.8
通讯作者：
Nuernberg, Peter
中科院分区：
文献类型：
--
作者：
Rutsch, Frank;Gailus, Susann;Nuernberg, Peter
维生素B-12（钴胺素）在动物中对于支链氨基酸和奇数链脂肪酸的代谢以及同型半胱氨酸再甲基化为甲硫氨酸至关重要（1）。在维生素B-12代谢的cblF先天性缺陷中，游离维生素在溶酶体中积累，从而阻碍其转化为辅因子（2，3）。利用12个无关cblF个体的纯合性作图和微细胞介导的染色体转移，我们在染色体6 q13上鉴定了一个候选基因，LMBRD 1，编码LMBD 1，LMBD 1是一种与脂质运载蛋白膜受体LMR同源的溶酶体膜蛋白。我们确定了LMBRD 1中5种不同的移码突变，导致LMBD 1功能丧失，24条疾病染色体中有18条携带相同的突变，嵌入一个共同的1.34 Mb单倍型。用野生型LMBD 1转染具有cblF的个体的成纤维细胞拯救钴胺素辅酶合成和功能。这项工作确定LMBRD 1作为钴胺素代谢的cblF缺陷的基础基因，并表明LMBD 1是钴胺素的溶酶体膜输出蛋白。
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.