LMBRD1: the gene for the cblF defect of vitamin B₁₂ metabolism

To date, only very few genetic disorders due to defects in lysosomal membrane transport are known. This paper reviews the identification of the underlying molecular defect causing an intriguing inborn error of vitamin B₁₂ metabolism, namely, defective lysosomal release of vitamin B ? (cblF defect). Using microcell-mediated chromosome transfer of wild-type human chromosomes into immortalized fibroblasts from a cblF patient and genome-wide homozygosity mapping in 12 unrelated cblF patients, we identified LMBRD1 as a positional candidate gene on chromosome 6q13. Five different frameshift mutations leading to loss of function of both LMBRD1 alleles were detected in the affected patients. Transfection of the LMBRD1 wild-type construct into fibroblasts derived from cblF patients restored cobalamin coenzyme synthesis and function. LMBRD1 encodes a novel lysosomal membrane protein with significant homology to lipocalin membrane receptors. These studies give further insight into the intracellular transport of vitamins, challenge the views on lipocalin receptors, and add to our understanding of lysosomal diseases.