Alternative titles; symbols
HGNC Approved Gene Symbol: LMBRD1
Cytogenetic location: 6q13 Genomic coordinates (GRCh38) : 6:69,674,010-69,797,010 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q13 | Methylmalonic aciduria and homocystinuria, cblF type | 277380 | Autosomal recessive | 3 |
LMBRD1 encodes a putative lysosomal cobalamin exporter (Rutsch et al., 2009).
Using a yeast 2-hybrid screen of a liver cDNA expression library to identify cellular factors that interact with the nuclear export signal (NES) at the C terminus of the large form of hepatitis delta antigen (HDAg-L), followed by RT-PCR and RACE, Wang et al. (2005) cloned LMBRD1, which they called NESI. The predicted 467-amino acid protein has a putative actin-binding site and a putative nuclear bipartite targeting signal. Northern blot analysis detected a 1.9-kb NESI transcript in a liver cell line and liver tissue, but not in other human tissues examined.
Rutsch et al. (2009) identified LMBRD1 as a candidate gene on chromosome 6 for the cblF inborn error of vitamin B12 metabolism (277380). The protein encoded by LMBRD1, which the authors called LMBD1, contains 540 amino acids and has a calculated molecular mass of 61.4 kD. It contains 9 predicted transmembrane domains and 6 putative N-glycosylation sites. In transfected HeLa cells and primary human fibroblasts, fluorescence-tagged LMBD1 exhibited a punctate distribution throughout the cytoplasm and perinuclear region that colocalized with a lysosomal marker. Electron microscopy and immunogold labeling showed that LMBD1 localized to the lysosomal membrane. Analysis of LMBD1 glycosylation status confirmed that LMBD1 has 9 transmembrane helices, with an N terminus in the lysosomal interior and a cytoplasmic C terminus.
Tseng et al. (2013) stated that the predicted 540-amino acid human LMBD1 protein contains 9 transmembrane domains, 2 putative AP2 (see 601024)-binding motifs, and a putative clathrin (see 118955) box. Lmbd1 localized in multiple membrane-bound organelles, including the lysosome and plasma membrane, of HL-1 mouse cardiac muscle cells.
Using whole-mount in situ hybridization, Buers et al. (2016) found that Lmbrd1 was ubiquitously expressed in early mouse embryos, with strongest expression in primitive streak and in extraembryonic tissue at embryonic day 7.5 (E7.5). Lmbrd1 expression was highest in neuronal fold at E8.5.
Rutsch et al. (2009) determined that the LMBRD1 gene contains 16 coding exons.
By genomic sequence analysis, Rutsch et al. (2009) mapped the LMBRD1 gene to chromosome 6q13.
By coimmunoprecipitation and Western blot analysis, Wang et al. (2005) showed that NESI interacted with full-length HDAg-L containing NES. Immunofluorescence microscopy demonstrated colocalization of NESI and HDAg-L in nuclei of infected hepatocytes. NESI-antisense treatment blocked the release of hepatitis delta virus genomic RNA mediated by HDAg-L. Wang et al. (2005) proposed that NESI plays an important role in the formation of a functionally competent export/package complex of HDAg-L.
Tseng et al. (2013) found that glucose uptake was upregulated in Lmbrd1 +/- mice. However, Lmbrd1 +/- mice were unresponsive when additional insulin was administered, suggesting that the signal that caused the increase in glucose uptake resulted from a disturbance of insulin receptor (INSR; 147670) signaling. Moreover, Lmbrd1 knockdown activated Insr signaling pathways in rat cardiomyocytes, suggesting that Lmbd1 participated in the regulation of Insr signaling. Further analysis showed that Lmbd1 selectively interacted with Insr to participate in the Insr internalization process. Lmbd1 interacted with AP2 to regulate insulin-induced clathrin-mediated endocytosis of Insr through its participation in clathrin-coated vesicles.
Using immunoprecipitation and confocal microscopy analyses in human hepatoma and embryonic kidney cells and Chinese hamster ovary cells, Kawaguchi et al. (2016) demonstrated that ABCD4 (603214) interacted with LMBD1 and then localized to lysosomes in a manner dependent on the lysosome targeting ability of LMBD1. Knockout of LMBRD1 disturbed ABCD4 localization to lysosomes, but not to the endoplasmic reticulum (ER). Kawaguchi et al. (2016) concluded that translocation of ABCD4 from the ER to lysosomes requires, at least in part, LMBD1.
In 12 unrelated patients with methylmalonic aciduria and homocystinuria type cblF (MAHCF; 277380), Rutsch et al. (2009) identified 5 different homozygous or compound heterozygous mutations in the LMBRD1 gene (612625.0001-612625.0003). A 1-bp deletion (612625.0001) was present in 18 of the 24 disease chromosomes, consistent with a common founder of European ancestry. All mutations were truncating, but the phenotype was variable, ranging from developmental delay to asymptomatic long-term survival; thus there were no genotype/phenotype correlations.
Buers et al. (2016) found that homozygous loss of Lmbrd1 resulted in early embryonic lethality, whereas heterozygous mice were healthy and fertile. Whole-mount in situ hybridization analysis for Bmp4 (112262) and Nodal (601265) expression demonstrated that initial formation of the proximal-distal axis was unaffected by loss of Lmbrd1. However, expression of Evx1 (142996) and Fgf8 (600483) was strongly reduced in Lmbrd1 -/- mice, indicating perturbation of dorsal-ventral axis formation and initiation of gastrulation. Buers et al. (2016) concluded that LMBRD1 function is essential for initiation of gastrulation.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human LMBRD1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In 7 patients with methylmalonic aciduria and homocystinuria type cblF (MAHCF; 277380), Rutsch et al. (2009) identified a homozygous 1-bp deletion (1056delG) in the LMBRD1 gene, resulting in a frameshift and premature termination. Four additional patients were compound heterozygous for the 1056delG mutation and another pathogenic mutation in the LMBRD1 gene (e.g., 612625.0003). The mutation was present in 18 of the 24 disease chromosomes, consistent with a common founder of European ancestry. The phenotype was variable, ranging from developmental delay to asymptomatic long-term survival. In vitro functional expression studies in patient cells showed that the biochemical defect could be rescued by transfection of the wildtype protein.
In a Hispanic boy with methylmalonic aciduria and homocystinuria, type cblF (MAHCF; 277380), Rutsch et al. (2009) identified a homozygous 2-bp deletion (515delAC) in the LMBRD1 gene, resulting in a frameshift and premature termination. He was small for gestational age, had short stature, tracheoesophageal fistula, and a complex congenital heart defect, and died at age 9 months after cardiac surgery.
In a German boy with methylmalonic aciduria and homocystinuria type cblF (MAHCF; 277380), Rutsch et al. (2009) identified compound heterozygosity for a 1-bp deletion (404delC) in the LMBRD1 gene, resulting in a frameshift and premature termination, and the 1056delG mutation (612625.0001). He had intrauterine growth retardation, was small for gestational age, and had feeding abnormalities. In vitro functional expression studies in patient cells showed that the biochemical defect could be rescued by transfection of the wildtype protein.
Buers, I., Pennekamp, P., Nitschke, Y., Lowe, C., Skryabin, B. V., Rutsch, F. Lmbrd1 expression is essential for the initiation of gastrulation. J. Cell. Molec. Med. 20: 1523-1533, 2016. [PubMed: 27061115] [Full Text: https://doi.org/10.1111/jcmm.12844]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Kawaguchi, K., Okamoto, T., Morita, M., Imanaka, T. Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1. Sci. Rep. 6: 30183, 2016. Note: Electronic Article. [PubMed: 27456980] [Full Text: https://doi.org/10.1038/srep30183]
Rutsch, F., Gailus, S., Miousse, I. R., Suormala, T., Sagne, C., Toliat, M. R., Nurnberg, G., Wittkampf, T., Buers, I., Sharifi, A., Stucki, M., Becker, C., Baumgartner, M., Robenek, H., Marquardt, T., Hohne, W., Gasnier, B., Rosenblatt, D. S., Fowler, B., Nurnberg, P. Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nature Genet. 41: 234-239, 2009. [PubMed: 19136951] [Full Text: https://doi.org/10.1038/ng.294]
Tseng, L. T., Lin, C. L., Tzen, K. Y., Chang, S. C., Chang, M. F. LMBD1 protein serves as a specific adaptor for insulin receptor internalization. J. Biol. Chem. 288: 32424-32432, 2013. [PubMed: 24078630] [Full Text: https://doi.org/10.1074/jbc.M113.479527]
Wang, Y.-H., Chang, S. C., Huang, C., Li, Y.-P., Lee, C.-H., Chang, M.-F. Novel nuclear export signal-interacting protein, NESI, critical for the assembly of hepatitis delta virus. J. Virol. 79: 8113-8120, 2005. [PubMed: 15956556] [Full Text: https://doi.org/10.1128/JVI.79.13.8113-8120.2005]