Alternative titles; symbols
HGNC Approved Gene Symbol: BLVRA
SNOMEDCT: 771441005;
Cytogenetic location: 7p13 Genomic coordinates (GRCh38): 7:43,758,122-43,807,342 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p13 | Hyperbiliverdinemia | 614156 | Autosomal dominant; Autosomal recessive | 3 |
Biliverdin reductases, such as BLVRA (EC 1.3.1.24), catalyze the conversion of biliverdin to bilirubin in the presence of NADPH or NADH (Komuro et al., 1996).
Meera Khan et al. (1983) used a simple chromogenic staining procedure for specific identification of BLVR after gel electrophoresis. The study indicated that both NADH-dependent and NADPH-dependent BLVR activity is due to 1 enzyme which is probably coded by a single gene and is a monomer in its functional configuration.
By RT-PCR of erythroleukemia cell line RNA, followed by screening a cDNA library of a second human leukemia cell line, Komuro et al. (1996) cloned BLVRA, which they called biliverdin IX-alpha reductase. The deduced 296-amino acid protein has a calculated molecular mass of 33.2 kD. Removal of 2 N-terminal amino acids results in a 294-amino acid mature protein with an N-terminal threonine. The N-terminal region contains the NADH/NADPH-binding consensus sequence. BLVRA shares 82.8% amino acid identity with rat Blvra, but it does not share significant homology with BLVRB (600941). Northern blot analysis detected BLVRA at 1.35 kb in all 8 tissues examined. Expression was highest in brain, pancreas, and lung, and lowest in liver and placenta.
By RT-PCR, Maines et al. (1996) cloned BVR from placenta RNA. Northern blot analysis detected BVR at about 1.2 kb in kidney mRNA. Western blot analysis detected a single protein, but isoelectric focusing detected several charge variants. Atomic absorption spectroscopy indicated that the protein purified from human liver contains zinc at an approximately 1:1 molar ratio.
Lerner-Marmarosh et al. (2005) found that BVR shares similarity with insulin receptor (INSR; 147670) in residues necessary for tyrosine kinase activity. The C terminus of BVR contains a 6-stranded beta sheet that may provide a docking site or protein-protein interaction site.
Gafvels et al. (2009) noted that the BLVRA gene contains 7 exons.
Hartz (2011) mapped the BLVRA gene to chromosome 7p13 based on an alignment of the BLVRA sequence (GenBank U34877) with the genomic sequence (GRCh37).
Through a study of mouse-human hybrids, Meera Khan et al. (1982) assigned the structural gene for biliverdin reductase to chromosome 7 (7p14-cen). Peters et al. (1989) mapped Blvr to mouse chromosome 2 using an electrophoretic variant in linkage studies.
Thomas et al. (2003) described the sequencing and annotation of a 341-kb region of mouse chromosome 2 containing 9 genes, including Blvra, and its comparison with the orthologous regions of the human and rat genomes. These analyses revealed that the conserved synteny between mouse chromosome 2 and human chromosome 7 reflects an interval containing a single gene (Blvra/BLVRA) that is, at most, only 34 kb in the mouse genome. In the mouse, this segment is flanked proximally by genes orthologous to human chromosome 15q21 and distally by genes orthologous to human chromosome 2q11. These findings illustrated that some small genomic regions outside the large mouse-human conserved segments can contain a single gene as well as sequences that are apparently unique to 1 genome.
Maines et al. (1996) found that zinc inhibited NADPH-dependent but not NADH-dependent reductase activity, suggesting that the NADH- and NADPH-binding regions differ in their ability to interact with zinc. Fe-hematoporphyrin, however, inhibited both NADH- and NADPH-dependent activity.
Bilirubin is a potent antioxidant that Baranano et al. (2002) showed can protect cells from a 10,000-fold excess of H2O2. They reported that bilirubin is a major physiologic antioxidant cytoprotectant. Cellular depletion of bilirubin in HeLa cells by BVRA RNA interference markedly augmented tissue levels of reactive oxygen species and caused apoptotic cell death. Depletion of glutathionine, generally regarded as a physiologic antioxidant cytoprotectant, elicited lesser increases in reactive oxygen species and cell death. The potent physiologic antioxidant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxidant, is itself oxidized to biliverdin and then recycled by biliverdin reductase back to bilirubin. Baranano et al. (2002) concluded that this redox cycle may constitute the principal physiologic function of bilirubin.
Lerner-Marmarosh et al. (2005) found that recombinant BVR was phosphorylated by INSR on tyr198, tyr228, and tyr291 in vitro. In addition to its reductase activity, BVR showed phosphatase activity against an insulin receptor substrate, IRS1 (147545), as well as test substrates, and it phosphorylated itself on tyr72 and tyr83. BVR serine phosphorylated IRS1, and point mutations of serine residues in the kinase domain of the reductase inhibited phosphotransferase activity. Autophosphorylation was activated by Mn(2+) but not other divalent cations tested, and Zn(2+) was inhibitory. Treatment of human embryonic kidney cells with insulin led to increased BVR reductase activity due to BVR phosphorylation by INSR, and knockdown of BVR by small interfering RNA significantly increased insulin-mediated glucose uptake. Since tyrosine phosphorylation of IRS1 activates the insulin signaling pathway and serine phosphorylation of IRS1 blocks insulin action, Lerner-Marmarosh et al. (2005) concluded that BVR has a potential antagonistic role in the insulin signaling pathway.
Using immunoprecipitation analysis, Lerner-Marmarosh et al. (2008) found that BVR interacted with ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) in BVR-transfected HEK293 cells treated with IGF1 (147440). BVR formed a ternary complex with ERK and MEK1 (MAP2K1; 176872), activated MEK1 and ERK1/ERK2 kinase activities, and was phosphorylated by ERK1/ERK2. Protein-protein interactions were required for BVR activation of MEK1 and ERK, and an intact BVR ATP-binding domain was necessary for MEK1-mediated ELK1 (311040) activation. Two MAPK docking consensus sequences in BVR, called the C box and D box, were required for interaction with ERK, and interaction at each site was critical for ERK/ELK1 activation. Transfection of BVR with a C-box mutation or of peptides corresponding to the C or D box blocked activation of ERK by IGF1. Transfection of BVR with a D-box mutation prevented activation of ERK by wildtype BVR and dramatically decreased ELK1 transcriptional activity. Experiments in which the BVR nuclear export signal or nuclear localization signal were mutated demonstrated the critical role of BVR in the nuclear localization of IGF-stimulated ERK for ELK1 activation. Small interfering RNA against BVR blocked activation of ERK and ELK1 by IGF1 and prevented formation of the ternary complex of MEK, ERK, and BVR. Lerner-Marmarosh et al. (2008) concluded that BVR has a critical role in the ERK signaling pathway.
In a 63-year-old Swedish man with liver failure and hyperbiliverdinemia (HBLVD; 614156) manifest as green jaundice, Gafvels et al. (2009) identified a heterozygous truncating mutation in the BLVRA gene (R18X; 109750.0001). His 2 children were also heterozygous for the mutation but had no clinical signs of liver disease and had normal levels of serum biliverdin. Gafvels et al. (2009) noted that the green jaundice in this patient was only apparent in the context of liver decompensation.
In 2 unrelated Inuit women from Greenland with episodic hyperbiliverdinemia associated with obstructive cholestasis due to gallstones, Nytofte et al. (2011) identified a homozygous truncating mutation in the BLVRA gene (S44X; 109750.0002). The findings indicated that complete loss of BLVRA activity is a nonlethal condition.
In a 63-year-old Swedish man with liver failure and hyperbiliverdinemia manifested as green jaundice (HBLVD; 614156), Gafvels et al. (2009) identified a heterozygous 52C-T transition in exon 2 of the BLVRA gene, resulting in an arg18-to-ter (R18X) substitution predicted to truncate the protein N-terminal to the active site tyr97. The mutation was not found in 200 controls or 9 patients with end-stage liver cirrhosis. His 2 children were also heterozygous for the mutation but had no clinical signs of liver disease and had normal levels of serum biliverdin. The patient had a history of cholecystectomy and of heavy alcohol consumption. He developed bleeding esophageal varices, ascites, cirrhotic liver failure, and encephalopathy, and died. During the final months of his life, he had green-tainted skin, sclerae, urine, and ascitic fluid. Laboratory studies showed elevated liver enzymes with normal serum levels of bilirubin. Liquid chromatography and mass spectrometry identified the green plasma and urine component as unconjugated biliverdin, which was significantly increased compared to controls. Gafvels et al. (2009) noted that the green jaundice in this patient was only apparent in the context of liver decompensation.
In 2 unrelated Inuit women from Greenland with episodic hyperbiliverdinemia manifested as green jaundice (HBLVD; 614156), Nytofte et al. (2011) identified a homozygous 214C-A transversion in exon 3 of the BLVRA gene, resulting in a ser44-to-ter (S44X) substitution. In vitro functional expression studies in Xenopus oocytes showed that the truncated mutant protein had no residual enzyme activity. Both women presented with obstructive cholestasis due to multiple gallstones; 1 was pregnant at the time. Both had significantly increased biliverdin in bodily fluids, but only 1 had increased serum bilirubin. The green jaundice resolved in both patients after resolution of the cholestasis. Family analysis of 1 of the women showed that each unaffected parent was heterozygous for the mutation. Her sister, who was also homozygous for the mutation, did not have green jaundice or biliary obstruction but did have a solitary stone in the gallbladder and had biliverdin concentrations 3-fold higher than controls.
Baranano, D. E., Rao, M., Ferris, C. D., Snyder, S. H. Biliverdin reductase: a major physiologic cytoprotectant. Proc. Nat. Acad. Sci. 99: 16093-16098, 2002. [PubMed: 12456881] [Full Text: https://doi.org/10.1073/pnas.252626999]
Gafvels, M., Holmstrom, P., Somell, A., Sjovall, F., Svensson, J.-O., Stahle, L., Broome, U., Stal, P. A novel mutation in the biliverdin reductase-A gene combined with liver cirrhosis results in hyperbiliverdinaemia (green jaundice). Liver Int. 29: 1116-1124, 2009. [PubMed: 19580635] [Full Text: https://doi.org/10.1111/j.1478-3231.2009.02029.x]
Hartz, P. A. Personal Communication. Baltimore, Md. 8/16/2011.
Komuro, A., Tobe, T., Nakano, Y., Yamaguchi, T., Tomita, M. Cloning and characterization of the cDNA encoding human biliverdin-IX-alpha reductase. Biochim. Biophys. Acta 1309: 89-99, 1996. [PubMed: 8950184] [Full Text: https://doi.org/10.1016/s0167-4781(96)00099-1]
Lerner-Marmarosh, N., Miralem, T., Gibbs, P. E. M., Maines, M. D. Human biliverdin reductase is an ERK activator; hBVR is an ERK nuclear transporter and is required for MAPK signaling. Proc. Nat. Acad. Sci. 105: 6870-6875, 2008. [PubMed: 18463290] [Full Text: https://doi.org/10.1073/pnas.0800750105]
Lerner-Marmarosh, N., Shen, J., Torno, M. D., Kravets, A., Hu, Z., Maines, M. D. Human biliverdin reductase: a member of the insulin receptor substrate family with serine/threonine/tyrosine kinase activity. Proc. Nat. Acad. Sci. 102: 7109-7114, 2005. [PubMed: 15870194] [Full Text: https://doi.org/10.1073/pnas.0502173102]
Maines, M. D., Polevoda, B. V., Huang, T. J., McCoubrey, W. K., Jr. Human biliverdin-IX-alpha reductase is a zinc-metalloprotein: characterization of purified Escherichia coli expressed enzymes. Europ. J. Biochem. 235: 372-381, 1996. [PubMed: 8631357] [Full Text: https://doi.org/10.1111/j.1432-1033.1996.00372.x]
Meera Khan, P., Wijnen, L. M. M., Wijnen, J. T., Grzeschik, K.-H. Assignment of a human biliverdin reductase gene (BLVR) to 7p14-cen. (Abstract) Cytogenet. Cell Genet. 32: 298 only, 1982.
Meera Khan, P., Wijnen, L. M. M., Wijnen, J. T., Grzeschik, K.-H. Electrophoretic characterization and genetics of human biliverdin reductase (BLVR; EC 1.3.1.24); assignment of BLVR to the p14-cen region of human chromosome 7 in mouse-human somatic cell hybrids. Biochem. Genet. 21: 123-133, 1983. [PubMed: 6838484]
Nytofte, N. S., Serrano, M. A., Monte, M. J., Gonzalez-Sanchez, E., Tumer, Z., Ladefoged, K., Briz, O., Marin, J. J. G. A homozygous nonsense mutation (c.214C-A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis. J. Med. Genet. 48: 219-225, 2011. [PubMed: 21278388] [Full Text: https://doi.org/10.1136/jmg.2009.074567]
Parkar, M., Jeremiah, S. J., Povey, S., Lee, A. F., Finlay, F. O., Goodfellow, P. N., Solomon, E. Confirmation of the assignment of human biliverdin reductase to chromosome 7. Ann. Hum. Genet. 48: 57-60, 1984. [PubMed: 6585176] [Full Text: https://doi.org/10.1111/j.1469-1809.1984.tb00834.x]
Peters, J., Ball, S. T., von Deimling, A. Localization of Blvr, biliverdin reductase, on mouse chromosome 2. Genomics 5: 270-274, 1989. [PubMed: 2793182] [Full Text: https://doi.org/10.1016/0888-7543(89)90057-8]
Thomas, J. W., NISC Comparative Sequencing Program, Green, E. D. Comparative sequence analysis of a single-gene conserved segment in mouse and human. Mammalian Genome 14: 673-678, 2003. [PubMed: 14694903] [Full Text: https://doi.org/10.1007/s00335-003-2300-1]