Abstract
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 B12 (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.
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Abbreviations
- Adocbl:
-
Deoxyadenosylcobalamin
- OHcbl:
-
Hydroxocobalamin
- LMBRD1, LMBD1:
-
LMBR1 domain containing 1
- LMBR:
-
Limb region 1
- LIMR:
-
Lipocalin-interacting membrane receptor
- Mecbl:
-
Methylcobalamin
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Acknowledgment
We are indebted to numerous collaborators for participation in the studies on the cblF defect. We particularly thank Peter Nürnberg and his coworkers Gudrun Nürnberg, Mohammad Reza Toliat, and Christian Becker for performing the linkage analysis, and David Rosenblatt and Isabelle Racine-Miousse for sharing patient material and performing the microcell-mediated chromosome transfer studies. Also, we express our thanks to Matthias Baumgartner and his coworker Martin Stucki for preparation of the LMBRD1 wild-type construct. Furthermore, we thank Bruno Gasnier, Corinne Sagné, Horst Robenek, and Insa Buers for performing the colocalization experiments. We are also thankful to Tanja Wittkampf for expert data collection and data analysis and to Thorsten Marquardt for help with the study design. Finally, we express our thanks to the parents and the affected patients for participating in our studies and to the clinicians, including D. Applegarth, J. Bever, S. Cederbaum, G. Davidson, B.S. Dowton, G. Hoganson, R. Lafromboise, U. Lichter, M. Lindner, M. Seashore, V. Shih, G.P.A. Smit, J. Vockley, H.E. Wiltse, and J.B. Hennermann, who provided patient samples and/or clinical information. FR and SG are supported by funds from “Innovative Medical Research” of the University of Münster Medical School, FR is supported by the Interdisciplinary Center for Clinical Research, Münster University. TS and BF are supported by the Swiss National Science Foundation.
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Communicated by: Henk Blom
Competing interest: None declared.
Accession codes cblF defect: OMIM #277380; GenBank: LMBRD1, 55788; LMBD1, NP_060838.2; LMBR1, NP_071903 ; LIMR, NP_060583
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Rutsch, F., Gailus, S., Suormala, T. et al. LMBRD1: the gene for the cblF defect of vitamin B12 metabolism. J Inherit Metab Dis 34, 121–126 (2011). https://doi.org/10.1007/s10545-010-9083-9
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DOI: https://doi.org/10.1007/s10545-010-9083-9