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9.A.54 The Lysosomal Cobalamin (B12) Transporter (L-B12T) Family

Vitamin B12 (cobalamin) is essential in animals for metabolism of branched chain amino acids and odd chain fatty acids, and for remethylation of homocysteine to methionine. The putative lysosomal cobalamin transporter of animals (and possibly other eukaryotes), in humans, when defective, gives rise to cobalamin F-type disease (Ruivo et al., 2009; Rutsch et al., 2010). The protein has 9 TMSs as do many of its homologues. Transmembrane proteins showing sequence similarity are present in most types of eukaryotes as well as bacteria. Some of the latter resemble ABC-type transporters (e.g., 3.A.1.128.2) and RodA of E. coli (9.B.3.1.2).

In the cblF inborn error of vitamin B12 metabolism, free vitamin accumulates in lysosomes, thus hindering its conversion to cofactors. Using homozygosity mapping in 12 unrelated cblF individuals and microcell-mediated chromosome transfer, Rutsch et al., 2009 identified a candidate gene on chromosome 6q13, LMBRD1, encoding LMBD1, a lysosomal membrane protein with homology to the lipocalin membrane receptor LIMR. They 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. Thus, LMBRD1 is the gene underlying the cblF defect of cobalamin metabolism and suggests that LMBD1 is a lysosomal membrane exporter for cobalamin.

The reaction proposed to be catalyzed is:

Cobalamin (out) → Cobalamin (in)

References associated with 9.A.54 family:

Braz, S.V., R.A. Benicio, G.S.S.S. Tonelli, S.N. Báo, P.N. Moretti, A. Pic-Taylor, S.F. Oliveira, A.C. Acevedo, I.M.C. Costa, and J.F. Mazzeu. (2022). Cobalamin F deficiency in a girl with severe skin hyperpigmentation and a homozygous LMBRD1 variant. Clin Exp Dermatol 47: 812-815. 34958133
Gailus, S., W. Höhne, B. Gasnier, P. Nürnberg, B. Fowler, and F. Rutsch. (2010). Insights into lysosomal cobalamin trafficking: lessons learned from cblF disease. J Mol Med (Berl) 88: 459-466. 20174775
Malhotra, A., A. Ziegler, L. Shu, R. Perrier, L. Amlie-Wolf, E. Wohler, N. Lygia de Macena Sobreira, E. Colin, A. Vanderver, O. Sherbini, K. Stouffs, E. Scalais, A. Serretti, M. Barth, B. Navet, P. Rollier, H. Xi, H. Wang, H. Zhang, D.L. Perry, A. Ferrarini, R. Colombo, A. Pepler, A. Schneider, K. Tomiwa, N. Okamoto, N. Matsumoto, N. Miyake, R. Taft, X. Mao, and D. Bonneau. (2021). De novo missense variants in are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features. J Med Genet 58: 712-716. 32820033
Paek, J., M. Kalocsay, D.P. Staus, L. Wingler, R. Pascolutti, J.A. Paulo, S.P. Gygi, and A.C. Kruse. (2017). Multidimensional Tracking of GPCR Signaling via Peroxidase-Catalyzed Proximity Labeling. Cell 169: 338-349.e11. 28388415
Ruivo, R., C. Anne, C. Sagné, and B. Gasnier. (2009). Molecular and cellular basis of lysosomal transmembrane protein dysfunction. Biochim. Biophys. Acta. 1793: 636-649. 19146888
Rutsch F., Gailus S., Suormala T. and Fowler B. (2011). LMBRD1: the gene for the cblF defect of vitamin B metabolism. J Inherit Metab Dis. 34(1):121-6. 20446115
Rutsch, F., S. Gailus, I.R. Miousse, T. Suormala, C. Sagné, M.R. Toliat, G. Nürnberg, T. Wittkampf, I. Buers, A. Sharifi, M. Stucki, C. Becker, M. Baumgartner, H. Robenek, T. Marquardt, W. Höhne, B. Gasnier, D.S. Rosenblatt, B. Fowler, and P. Nürnberg. (2009). Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat. Genet. 41: 234-239. 19136951
Wilcken, B. (2012). Leukoencephalopathies associated with disorders of cobalamin and folate metabolism. Semin Neurol 32: 68-74. 22422209