Defective LMBRD1 does not transport lysosomal Cbl to cytosol

Stable Identifier
Reaction [transition]
Homo sapiens
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The probable lysosomal cobalamin transporter (LMBD1) is the most likely candidate to transport cobalamin (Cbl) from inside the lysosome to the cytosol (Rutsch et al. 2009). From here, Cbl can either be used to synthesize the essential cofactors for methionine synthase in the cytosol or methylmalonyl CoA mutase in the mitochondria or, it can be transported out of the cell to tissues that require Cbl. Defects in LMBRD1 (the gene that encodes LMBD1) cause methylmalonic aciduria and homocystinuria type cblF (MMAHCF; MIM:277380), characterised biochemically by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MetCbl) and also by accumulation of large amounts of unmetabolized Cbl in lysosomes; this is the critical finding that differentiates cblF and cblJ from other inborn errors of Cbl (Rutsch et al. 2009, Gailus et al. 2010). Rutsch et al. identified a 1 bp deletion (1056delG) in the LMBRD1 gene, resulting in a frameshift and premature truncation. This common mutation has a common founder of European ancestry. The phenotype is variable, ranging from developmental delay to asymptomatic long term survival (Rutsch et al. 2009).

There is a second protein that is also involved in this process, the ATP binding cassette transporter ABCD4. ABCD4 mutations underlie the recently described cblJ disorder, which is phenotypically very similar to cblF (not yet annotated, Coelho et al. 2012).

Literature References
PubMed ID Title Journal Year
19136951 Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism

Rutsch, F, Gailus, S, Miousse, IR, Suormala, T, Sagné, C, Toliat, MR, Nürnberg, G, Wittkampf, T, Buers, I, Sharifi, A, Stucki, M, Becker, C, Baumgartner, M, Robenek, H, Marquardt, T, Höhne, W, Gasnier, B, Rosenblatt, DS, Fowler, B, Nürnberg, P

Nat. Genet. 2009
22922874 Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism

Coelho, D, Kim, JC, Miousse, IR, Fung, S, du Moulin, M, Buers, I, Suormala, T, Burda, P, Frapolli, M, Stucki, M, Nürnberg, P, Thiele, H, Robenek, H, Höhne, W, Longo, N, Pasquali, M, Mengel, E, Watkins, D, Shoubridge, EA, Majewski, J, Rosenblatt, DS, Fowler, B, Rutsch, F, Baumgartner, MR

Nat. Genet. 2012
20174775 Insights into lysosomal cobalamin trafficking: lessons learned from cblF disease

Gailus, S, Höhne, W, Gasnier, B, Nürnberg, P, Fowler, B, Rutsch, F

J. Mol. Med. 2010
Participant Of
Catalyst Activity
Catalyst Activity
ATPase-coupled vitamin B12 transmembrane transporter activity of LMBRD1 L352fs*19 [lysosomal membrane]
Physical Entity
Normal reaction
Name Identifier Synonyms
methylmalonic aciduria and homocystinuria type cblF 0050717 Cobalamin F deficiency
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