Full text data of BLVRA
BLVRA
(BLVR, BVR)
[Confidence: high (present in two of the MS resources)]
Biliverdin reductase A; BVR A; 1.3.1.24 (Biliverdin-IX alpha-reductase; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Biliverdin reductase A; BVR A; 1.3.1.24 (Biliverdin-IX alpha-reductase; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00294158
IPI00294158 Biliverdin reductase A precursor heme metabolism, Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00294158 Biliverdin reductase A precursor heme metabolism, Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P53004
ID BIEA_HUMAN Reviewed; 296 AA.
AC P53004; A8K747; O95019; Q86UX0; Q96QL4; Q9BRW8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-OCT-2002, sequence version 2.
DT 22-JAN-2014, entry version 133.
DE RecName: Full=Biliverdin reductase A;
DE Short=BVR A;
DE EC=1.3.1.24;
DE AltName: Full=Biliverdin-IX alpha-reductase;
DE Flags: Precursor;
GN Name=BLVRA; Synonyms=BLVR, BVR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-3.
RX PubMed=8950184; DOI=10.1016/S0167-4781(96)00099-1;
RA Komuro A., Tobe T., Nakano Y., Yamaguchi T., Tomita M.;
RT "Cloning and characterization of the cDNA encoding human biliverdin-IX
RT alpha reductase.";
RL Biochim. Biophys. Acta 1309:89-99(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=8631357; DOI=10.1111/j.1432-1033.1996.00372.x;
RA Maines M.D., Polevoda B.V., Huang T.-J., McCoubrey W.K. Jr.;
RT "Human biliverdin IXalpha reductase is a zinc-metalloprotein.
RT Characterization of purified and Escherichia coli expressed enzymes.";
RL Eur. J. Biochem. 235:372-381(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-3; VAL-37 AND
RP ARG-56.
RG NIEHS SNPs program;
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-3.
RC TISSUE=Brain, and Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 3-36; 48-74 AND 228-248.
RC TISSUE=Liver;
RX PubMed=8424666; DOI=10.1006/abbi.1993.1044;
RA Maines M.D., Trakshel G.M.;
RT "Purification and characterization of human biliverdin reductase.";
RL Arch. Biochem. Biophys. 300:320-326(1993).
RN [8]
RP PROTEIN SEQUENCE OF 3-22.
RC TISSUE=Liver;
RX PubMed=7929092;
RA Yamaguchi T., Komoda Y., Nakajima H.;
RT "Biliverdin-IX alpha reductase and biliverdin-IX beta reductase from
RT human liver. Purification and characterization.";
RL J. Biol. Chem. 269:24343-24348(1994).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP INVOLVEMENT IN HBLVD.
RX PubMed=19580635; DOI=10.1111/j.1478-3231.2009.02029.x;
RA Gafvels M., Holmstrom P., Somell A., Sjovall F., Svensson J.O.,
RA Stahle L., Broome U., Stal P.;
RT "A novel mutation in the biliverdin reductase-A gene combined with
RT liver cirrhosis results in hyperbiliverdinaemia (green jaundice).";
RL Liver Int. 29:1116-1124(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-174 AND SER-178, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-248 AND LYS-253, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 7-296 IN COMPLEX WITH NADP.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human biliverdin reductase A.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Reduces the gamma-methene bridge of the open
CC tetrapyrrole, biliverdin IX alpha, to bilirubin with the
CC concomitant oxidation of a NADH or NADPH cofactor.
CC -!- CATALYTIC ACTIVITY: Bilirubin + NAD(P)(+) = biliverdin + NAD(P)H.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoheme
CC degradation.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Liver.
CC -!- DISEASE: Hyperbiliverdinemia (HBLVD) [MIM:614156]: A condition
CC characterized by a green discoloration of the skin, urine, serum,
CC and other bodily fluids. It is due to increased biliverdin
CC resulting from inefficient conversion to bilirubin. Affected
CC individuals appear to have symptoms only in the context of
CC obstructive cholestasis and/or liver failure. In some cases, green
CC jaundice can resolve after resolution of obstructive cholestasis.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: Uses the reactants NADH or NADPH depending on the
CC pH; NADH is used at the acidic pH range (6-6.9) and NADPH at the
CC alkaline range (8.5-8.7). NADPH, however, is the probable reactant
CC in biological systems.
CC -!- SIMILARITY: Belongs to the Gfo/Idh/MocA family. Biliverdin
CC reductase subfamily.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/blvra/";
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DR EMBL; U34877; AAC35588.1; -; mRNA.
DR EMBL; X93086; CAA63635.1; -; mRNA.
DR EMBL; AK291862; BAF84551.1; -; mRNA.
DR EMBL; AY616754; AAT11126.1; -; Genomic_DNA.
DR EMBL; AC005189; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC004939; AAD05025.1; -; Genomic_DNA.
DR EMBL; AC004985; AAP21879.1; -; Genomic_DNA.
DR EMBL; BC005902; AAH05902.1; -; mRNA.
DR EMBL; BC008456; AAH08456.1; -; mRNA.
DR PIR; G02066; G02066.
DR PIR; S62624; S62624.
DR RefSeq; NP_000703.2; NM_000712.3.
DR RefSeq; NP_001240752.1; NM_001253823.1.
DR UniGene; Hs.488143; -.
DR PDB; 2H63; X-ray; 2.70 A; A/B/C/D=7-296.
DR PDBsum; 2H63; -.
DR ProteinModelPortal; P53004; -.
DR SMR; P53004; 7-291.
DR DIP; DIP-42180N; -.
DR MINT; MINT-1212210; -.
DR STRING; 9606.ENSP00000265523; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P53004; -.
DR DMDM; 23830892; -.
DR OGP; P53004; -.
DR REPRODUCTION-2DPAGE; IPI00294158; -.
DR PaxDb; P53004; -.
DR PeptideAtlas; P53004; -.
DR PRIDE; P53004; -.
DR Ensembl; ENST00000265523; ENSP00000265523; ENSG00000106605.
DR Ensembl; ENST00000402924; ENSP00000385757; ENSG00000106605.
DR GeneID; 644; -.
DR KEGG; hsa:644; -.
DR UCSC; uc003tir.3; human.
DR CTD; 644; -.
DR GeneCards; GC07P043798; -.
DR HGNC; HGNC:1062; BLVRA.
DR HPA; HPA042865; -.
DR MIM; 109750; gene.
DR MIM; 614156; phenotype.
DR neXtProt; NX_P53004; -.
DR Orphanet; 276405; Hyperbiliverdinemia.
DR PharmGKB; PA25373; -.
DR eggNOG; NOG114525; -.
DR HOGENOM; HOG000231884; -.
DR HOVERGEN; HBG003218; -.
DR InParanoid; P53004; -.
DR KO; K00214; -.
DR OMA; KRILHCL; -.
DR OrthoDB; EOG78WKS5; -.
DR PhylomeDB; P53004; -.
DR BioCyc; MetaCyc:HS02928-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00684; -.
DR EvolutionaryTrace; P53004; -.
DR GenomeRNAi; 644; -.
DR NextBio; 2614; -.
DR PRO; PR:P53004; -.
DR ArrayExpress; P53004; -.
DR Bgee; P53004; -.
DR CleanEx; HS_BLVRA; -.
DR Genevestigator; P53004; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004074; F:biliverdin reductase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0042167; P:heme catabolic process; TAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR017094; Biliverdin_Rdtase_A.
DR InterPro; IPR015249; Biliverdin_Rdtase_cat.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR000683; Oxidoreductase_N.
DR Pfam; PF09166; Biliv-reduc_cat; 1.
DR Pfam; PF01408; GFO_IDH_MocA; 1.
DR PIRSF; PIRSF037032; Biliverdin_reductase_A; 1.
DR ProDom; PD040165; Biliverdin_Rdtase_cat; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Metal-binding; NAD; NADP; Oxidoreductase;
KW Phosphoprotein; Polymorphism; Reference proteome; Zinc.
FT PROPEP 1 2
FT /FTId=PRO_0000010852.
FT CHAIN 3 296 Biliverdin reductase A.
FT /FTId=PRO_0000010853.
FT NP_BIND 15 20 NAD or NADP.
FT NP_BIND 44 46 NAD or NADP.
FT NP_BIND 77 80 NAD or NADP.
FT COMPBIAS 11 16 Poly-Val.
FT METAL 280 280 Zinc (Potential).
FT METAL 281 281 Zinc (Potential).
FT METAL 292 292 Zinc (Potential).
FT METAL 293 293 Zinc (Potential).
FT BINDING 98 98 NAD or NADP; via carbonyl oxygen.
FT MOD_RES 174 174 Phosphothreonine.
FT MOD_RES 178 178 Phosphoserine.
FT MOD_RES 230 230 Phosphoserine.
FT MOD_RES 248 248 N6-acetyllysine.
FT MOD_RES 253 253 N6-acetyllysine.
FT VARIANT 3 3 A -> T (in dbSNP:rs699512).
FT /FTId=VAR_019230.
FT VARIANT 37 37 L -> V (in dbSNP:rs17245918).
FT /FTId=VAR_019231.
FT VARIANT 56 56 Q -> R (in dbSNP:rs1050916).
FT /FTId=VAR_014851.
FT CONFLICT 121 121 L -> S (in Ref. 6; AAH05902).
FT CONFLICT 154 155 AG -> SD (in Ref. 2; CAA63635).
FT CONFLICT 160 160 E -> D (in Ref. 2; CAA63635).
FT STRAND 9 14
FT HELIX 18 28
FT HELIX 33 36
FT STRAND 37 43
FT STRAND 50 53
FT HELIX 59 64
FT STRAND 70 73
FT HELIX 77 89
FT STRAND 93 98
FT HELIX 104 117
FT STRAND 121 124
FT HELIX 126 129
FT HELIX 131 140
FT STRAND 145 154
FT HELIX 159 162
FT HELIX 165 168
FT HELIX 170 180
FT STRAND 182 193
FT STRAND 198 207
FT STRAND 212 219
FT STRAND 226 235
FT HELIX 250 262
FT HELIX 268 290
SQ SEQUENCE 296 AA; 33428 MW; 2CF2AA7F1CDDB707 CRC64;
MNAEPERKFG VVVVGVGRAG SVRMRDLRNP HPSSAFLNLI GFVSRRELGS IDGVQQISLE
DALSSQEVEV AYICSESSSH EDYIRQFLNA GKHVLVEYPM TLSLAAAQEL WELAEQKGKV
LHEEHVELLM EEFAFLKKEV VGKDLLKGSL LFTAGPLEEE RFGFPAFSGI SRLTWLVSLF
GELSLVSATL EERKEDQYMK MTVCLETEKK SPLSWIEEKG PGLKRNRYLS FHFKSGSLEN
VPNVGVNKNI FLKDQNIFVQ KLLGQFSEKE LAAEKKRILH CLGLAEEIQK YCCSRK
//
ID BIEA_HUMAN Reviewed; 296 AA.
AC P53004; A8K747; O95019; Q86UX0; Q96QL4; Q9BRW8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-OCT-2002, sequence version 2.
DT 22-JAN-2014, entry version 133.
DE RecName: Full=Biliverdin reductase A;
DE Short=BVR A;
DE EC=1.3.1.24;
DE AltName: Full=Biliverdin-IX alpha-reductase;
DE Flags: Precursor;
GN Name=BLVRA; Synonyms=BLVR, BVR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-3.
RX PubMed=8950184; DOI=10.1016/S0167-4781(96)00099-1;
RA Komuro A., Tobe T., Nakano Y., Yamaguchi T., Tomita M.;
RT "Cloning and characterization of the cDNA encoding human biliverdin-IX
RT alpha reductase.";
RL Biochim. Biophys. Acta 1309:89-99(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=8631357; DOI=10.1111/j.1432-1033.1996.00372.x;
RA Maines M.D., Polevoda B.V., Huang T.-J., McCoubrey W.K. Jr.;
RT "Human biliverdin IXalpha reductase is a zinc-metalloprotein.
RT Characterization of purified and Escherichia coli expressed enzymes.";
RL Eur. J. Biochem. 235:372-381(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-3; VAL-37 AND
RP ARG-56.
RG NIEHS SNPs program;
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-3.
RC TISSUE=Brain, and Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 3-36; 48-74 AND 228-248.
RC TISSUE=Liver;
RX PubMed=8424666; DOI=10.1006/abbi.1993.1044;
RA Maines M.D., Trakshel G.M.;
RT "Purification and characterization of human biliverdin reductase.";
RL Arch. Biochem. Biophys. 300:320-326(1993).
RN [8]
RP PROTEIN SEQUENCE OF 3-22.
RC TISSUE=Liver;
RX PubMed=7929092;
RA Yamaguchi T., Komoda Y., Nakajima H.;
RT "Biliverdin-IX alpha reductase and biliverdin-IX beta reductase from
RT human liver. Purification and characterization.";
RL J. Biol. Chem. 269:24343-24348(1994).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP INVOLVEMENT IN HBLVD.
RX PubMed=19580635; DOI=10.1111/j.1478-3231.2009.02029.x;
RA Gafvels M., Holmstrom P., Somell A., Sjovall F., Svensson J.O.,
RA Stahle L., Broome U., Stal P.;
RT "A novel mutation in the biliverdin reductase-A gene combined with
RT liver cirrhosis results in hyperbiliverdinaemia (green jaundice).";
RL Liver Int. 29:1116-1124(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-174 AND SER-178, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-248 AND LYS-253, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 7-296 IN COMPLEX WITH NADP.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human biliverdin reductase A.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Reduces the gamma-methene bridge of the open
CC tetrapyrrole, biliverdin IX alpha, to bilirubin with the
CC concomitant oxidation of a NADH or NADPH cofactor.
CC -!- CATALYTIC ACTIVITY: Bilirubin + NAD(P)(+) = biliverdin + NAD(P)H.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoheme
CC degradation.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Liver.
CC -!- DISEASE: Hyperbiliverdinemia (HBLVD) [MIM:614156]: A condition
CC characterized by a green discoloration of the skin, urine, serum,
CC and other bodily fluids. It is due to increased biliverdin
CC resulting from inefficient conversion to bilirubin. Affected
CC individuals appear to have symptoms only in the context of
CC obstructive cholestasis and/or liver failure. In some cases, green
CC jaundice can resolve after resolution of obstructive cholestasis.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- MISCELLANEOUS: Uses the reactants NADH or NADPH depending on the
CC pH; NADH is used at the acidic pH range (6-6.9) and NADPH at the
CC alkaline range (8.5-8.7). NADPH, however, is the probable reactant
CC in biological systems.
CC -!- SIMILARITY: Belongs to the Gfo/Idh/MocA family. Biliverdin
CC reductase subfamily.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/blvra/";
CC -----------------------------------------------------------------------
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DR EMBL; U34877; AAC35588.1; -; mRNA.
DR EMBL; X93086; CAA63635.1; -; mRNA.
DR EMBL; AK291862; BAF84551.1; -; mRNA.
DR EMBL; AY616754; AAT11126.1; -; Genomic_DNA.
DR EMBL; AC005189; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC004939; AAD05025.1; -; Genomic_DNA.
DR EMBL; AC004985; AAP21879.1; -; Genomic_DNA.
DR EMBL; BC005902; AAH05902.1; -; mRNA.
DR EMBL; BC008456; AAH08456.1; -; mRNA.
DR PIR; G02066; G02066.
DR PIR; S62624; S62624.
DR RefSeq; NP_000703.2; NM_000712.3.
DR RefSeq; NP_001240752.1; NM_001253823.1.
DR UniGene; Hs.488143; -.
DR PDB; 2H63; X-ray; 2.70 A; A/B/C/D=7-296.
DR PDBsum; 2H63; -.
DR ProteinModelPortal; P53004; -.
DR SMR; P53004; 7-291.
DR DIP; DIP-42180N; -.
DR MINT; MINT-1212210; -.
DR STRING; 9606.ENSP00000265523; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P53004; -.
DR DMDM; 23830892; -.
DR OGP; P53004; -.
DR REPRODUCTION-2DPAGE; IPI00294158; -.
DR PaxDb; P53004; -.
DR PeptideAtlas; P53004; -.
DR PRIDE; P53004; -.
DR Ensembl; ENST00000265523; ENSP00000265523; ENSG00000106605.
DR Ensembl; ENST00000402924; ENSP00000385757; ENSG00000106605.
DR GeneID; 644; -.
DR KEGG; hsa:644; -.
DR UCSC; uc003tir.3; human.
DR CTD; 644; -.
DR GeneCards; GC07P043798; -.
DR HGNC; HGNC:1062; BLVRA.
DR HPA; HPA042865; -.
DR MIM; 109750; gene.
DR MIM; 614156; phenotype.
DR neXtProt; NX_P53004; -.
DR Orphanet; 276405; Hyperbiliverdinemia.
DR PharmGKB; PA25373; -.
DR eggNOG; NOG114525; -.
DR HOGENOM; HOG000231884; -.
DR HOVERGEN; HBG003218; -.
DR InParanoid; P53004; -.
DR KO; K00214; -.
DR OMA; KRILHCL; -.
DR OrthoDB; EOG78WKS5; -.
DR PhylomeDB; P53004; -.
DR BioCyc; MetaCyc:HS02928-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00684; -.
DR EvolutionaryTrace; P53004; -.
DR GenomeRNAi; 644; -.
DR NextBio; 2614; -.
DR PRO; PR:P53004; -.
DR ArrayExpress; P53004; -.
DR Bgee; P53004; -.
DR CleanEx; HS_BLVRA; -.
DR Genevestigator; P53004; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004074; F:biliverdin reductase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0042167; P:heme catabolic process; TAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR017094; Biliverdin_Rdtase_A.
DR InterPro; IPR015249; Biliverdin_Rdtase_cat.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR000683; Oxidoreductase_N.
DR Pfam; PF09166; Biliv-reduc_cat; 1.
DR Pfam; PF01408; GFO_IDH_MocA; 1.
DR PIRSF; PIRSF037032; Biliverdin_reductase_A; 1.
DR ProDom; PD040165; Biliverdin_Rdtase_cat; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Metal-binding; NAD; NADP; Oxidoreductase;
KW Phosphoprotein; Polymorphism; Reference proteome; Zinc.
FT PROPEP 1 2
FT /FTId=PRO_0000010852.
FT CHAIN 3 296 Biliverdin reductase A.
FT /FTId=PRO_0000010853.
FT NP_BIND 15 20 NAD or NADP.
FT NP_BIND 44 46 NAD or NADP.
FT NP_BIND 77 80 NAD or NADP.
FT COMPBIAS 11 16 Poly-Val.
FT METAL 280 280 Zinc (Potential).
FT METAL 281 281 Zinc (Potential).
FT METAL 292 292 Zinc (Potential).
FT METAL 293 293 Zinc (Potential).
FT BINDING 98 98 NAD or NADP; via carbonyl oxygen.
FT MOD_RES 174 174 Phosphothreonine.
FT MOD_RES 178 178 Phosphoserine.
FT MOD_RES 230 230 Phosphoserine.
FT MOD_RES 248 248 N6-acetyllysine.
FT MOD_RES 253 253 N6-acetyllysine.
FT VARIANT 3 3 A -> T (in dbSNP:rs699512).
FT /FTId=VAR_019230.
FT VARIANT 37 37 L -> V (in dbSNP:rs17245918).
FT /FTId=VAR_019231.
FT VARIANT 56 56 Q -> R (in dbSNP:rs1050916).
FT /FTId=VAR_014851.
FT CONFLICT 121 121 L -> S (in Ref. 6; AAH05902).
FT CONFLICT 154 155 AG -> SD (in Ref. 2; CAA63635).
FT CONFLICT 160 160 E -> D (in Ref. 2; CAA63635).
FT STRAND 9 14
FT HELIX 18 28
FT HELIX 33 36
FT STRAND 37 43
FT STRAND 50 53
FT HELIX 59 64
FT STRAND 70 73
FT HELIX 77 89
FT STRAND 93 98
FT HELIX 104 117
FT STRAND 121 124
FT HELIX 126 129
FT HELIX 131 140
FT STRAND 145 154
FT HELIX 159 162
FT HELIX 165 168
FT HELIX 170 180
FT STRAND 182 193
FT STRAND 198 207
FT STRAND 212 219
FT STRAND 226 235
FT HELIX 250 262
FT HELIX 268 290
SQ SEQUENCE 296 AA; 33428 MW; 2CF2AA7F1CDDB707 CRC64;
MNAEPERKFG VVVVGVGRAG SVRMRDLRNP HPSSAFLNLI GFVSRRELGS IDGVQQISLE
DALSSQEVEV AYICSESSSH EDYIRQFLNA GKHVLVEYPM TLSLAAAQEL WELAEQKGKV
LHEEHVELLM EEFAFLKKEV VGKDLLKGSL LFTAGPLEEE RFGFPAFSGI SRLTWLVSLF
GELSLVSATL EERKEDQYMK MTVCLETEKK SPLSWIEEKG PGLKRNRYLS FHFKSGSLEN
VPNVGVNKNI FLKDQNIFVQ KLLGQFSEKE LAAEKKRILH CLGLAEEIQK YCCSRK
//
MIM
109750
*RECORD*
*FIELD* NO
109750
*FIELD* TI
*109750 BILIVERDIN REDUCTASE A; BLVRA
;;BILIVERDIN IX-ALPHA REDUCTASE;;
BVR;;
BLVR;;
read moreBVRA
*FIELD* TX
DESCRIPTION
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).
CLONING
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.
GENE STRUCTURE
Gafvels et al. (2009) noted that the BLVRA gene contains 7 exons.
MAPPING
Hartz (2011) mapped the BLVRA gene to chromosome 7p13 based on an
alignment of the BLVRA sequence (GenBank 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.
GENE FUNCTION
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.
MOLECULAR GENETICS
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.
*FIELD* AV
.0001
HYPERBILIVERDINEMIA
BLVRA, ARG18TER
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.
.0002
HYPERBILIVERDINEMIA
BLVRA, SER44TER
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 gall bladder and had
biliverdin concentrations 3-fold higher than controls.
*FIELD* SA
Parkar et al. (1984)
*FIELD* RF
1. 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.
2. 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.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 8/16/2011.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Peters, J.; Ball, S. T.; von Deimling, A.: Localization of Blvr,
biliverdin reductase, on mouse chromosome 2. Genomics 5: 270-274,
1989.
13. 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.
*FIELD* CN
Cassandra L. Kniffin - updated: 8/9/2011
Patricia A. Hartz - updated: 2/12/2009
Patricia A. Hartz - updated: 8/2/2005
Victor A. McKusick - updated: 12/8/2003
Victor A. McKusick - updated: 1/15/2003
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 08/16/2011
wwang: 8/16/2011
wwang: 8/15/2011
ckniffin: 8/9/2011
mgross: 2/16/2009
terry: 2/12/2009
wwang: 8/11/2005
wwang: 8/2/2005
terry: 8/2/2005
tkritzer: 12/11/2003
terry: 12/8/2003
cwells: 1/16/2003
terry: 1/15/2003
carol: 4/8/1999
mark: 11/13/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/3/1989
root: 5/11/1989
*RECORD*
*FIELD* NO
109750
*FIELD* TI
*109750 BILIVERDIN REDUCTASE A; BLVRA
;;BILIVERDIN IX-ALPHA REDUCTASE;;
BVR;;
BLVR;;
read moreBVRA
*FIELD* TX
DESCRIPTION
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).
CLONING
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.
GENE STRUCTURE
Gafvels et al. (2009) noted that the BLVRA gene contains 7 exons.
MAPPING
Hartz (2011) mapped the BLVRA gene to chromosome 7p13 based on an
alignment of the BLVRA sequence (GenBank 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.
GENE FUNCTION
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.
MOLECULAR GENETICS
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.
*FIELD* AV
.0001
HYPERBILIVERDINEMIA
BLVRA, ARG18TER
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.
.0002
HYPERBILIVERDINEMIA
BLVRA, SER44TER
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 gall bladder and had
biliverdin concentrations 3-fold higher than controls.
*FIELD* SA
Parkar et al. (1984)
*FIELD* RF
1. 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.
2. 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.
3. Hartz, P. A.: Personal Communication. Baltimore, Md. 8/16/2011.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Peters, J.; Ball, S. T.; von Deimling, A.: Localization of Blvr,
biliverdin reductase, on mouse chromosome 2. Genomics 5: 270-274,
1989.
13. 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.
*FIELD* CN
Cassandra L. Kniffin - updated: 8/9/2011
Patricia A. Hartz - updated: 2/12/2009
Patricia A. Hartz - updated: 8/2/2005
Victor A. McKusick - updated: 12/8/2003
Victor A. McKusick - updated: 1/15/2003
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 08/16/2011
wwang: 8/16/2011
wwang: 8/15/2011
ckniffin: 8/9/2011
mgross: 2/16/2009
terry: 2/12/2009
wwang: 8/11/2005
wwang: 8/2/2005
terry: 8/2/2005
tkritzer: 12/11/2003
terry: 12/8/2003
cwells: 1/16/2003
terry: 1/15/2003
carol: 4/8/1999
mark: 11/13/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 8/3/1989
root: 5/11/1989
MIM
614156
*RECORD*
*FIELD* NO
614156
*FIELD* TI
#614156 HYPERBILIVERDINEMIA; HBLVD
;;GREEN JAUNDICE
*FIELD* TX
A number sign (#) is used with this entry because hyperbiliverdinemia
read more(HBLVD) can be caused by heterozygous or homozygous mutation in the gene
encoding bilirubin reductase-alpha (BLVRA; 109750) on chromosome 7p13.
DESCRIPTION
Hyperbiliverdinemia can manifest as green jaundice, which is a green
discoloration of the skin, urine, serum, and other bodily fluids, due to
increased biliverdin resulting from inefficient conversion to bilirubin.
Although rarely reported, affected individuals appear to have symptoms
only in the context of obstructive cholestasis and/or liver failure. In
some cases, green jaundice can resolve after resolution of obstructive
cholestasis. Green jaundice has also been associated with malnutrition,
medication, and congenital biliary atresia (summary by Huffman et al.,
2009).
CLINICAL FEATURES
Gafvels et al. (2009) reported a 63-year-old Swedish man with alcoholic
liver failure and hyperbiliverdinemia manifested as green jaundice. The
patient first presented with fatigue, weight, loss, and nausea, and
laboratory studies showed elevated liver enzymes with normal serum
levels of bilirubin. He had a history of cholecystectomy and of heavy
alcohol consumption. He developed bleeding esophageal varices, ascites,
cirrhotic liver failure, and fatal encephalopathy. During the final
months of his life, he had green-tainted skin, sclerae, urine, and
ascitic fluid. Liquid chromatography and mass spectrometry identified
the green plasma and urine component as unconjugated biliverdin, which
was significantly increased compared to controls.
Nytofte et al. (2011) reported 2 unrelated Inuit women from Greenland
with episodic hyperbiliverdinemia and green jaundice. Both presented
with obstructive cholestasis due to multiple gallstones; 1 was pregnant
at the time. A green color developed in the skin, urine, serum, and
bile, and in the milk from the pregnant woman. Laboratory studies showed
increased liver enzymes and biliverdin in bodily fluids, but only 1 had
increased serum bilirubin. The green discoloration resolved in both
patients after surgical resolution of cholestasis. Nytofte et al. (2011)
concluded that biliary obstruction was the primary event, and green
jaundice appeared as a consequence.
MOLECULAR GENETICS
In a 63-year-old Swedish man with liver failure and hyperbiliverdinemia
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). Family study of 1 of the
women showed that each unaffected parent was heterozygous for the
mutation. The patient's 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. The findings indicated that
complete loss of BLVRA activity is a nonlethal condition.
*FIELD* RF
1. 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.
2. Huffman, C.; Chillag, S.; Paulman, L.; McMahon, C.: It's not easy
bein' green. Am. J. Med. 122: 820-822, 2009.
3. 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.
*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive
ABDOMEN:
[Liver];
Liver dysfunction;
[Biliary tract];
Cholestasis;
Cholelithiasis
SKIN, NAILS, HAIR:
[Skin];
Jaundice, green
LABORATORY ABNORMALITIES:
Green urine;
Green serum;
Increased biliverdin in bodily fluids;
Bilirubin may or may not be increased
MISCELLANEOUS:
Three patients have been reported (as of August 2011);
Green jaundice occurs only in the context of liver failure or obstructive
cholestasis;
Green color resolves if cholestasis is treated;
Both heterozygous and homozygous mutations have been reported
MOLECULAR BASIS:
Caused by mutation in the biliverdin reductase A gene (BLVRA, 109750.0001)
*FIELD* CD
Cassandra L. Kniffin: 8/9/2011
*FIELD* ED
joanna: 12/29/2011
ckniffin: 8/9/2011
*FIELD* CD
Cassandra L. Kniffin: 8/9/2011
*FIELD* ED
carol: 08/16/2011
wwang: 8/15/2011
ckniffin: 8/9/2011
*RECORD*
*FIELD* NO
614156
*FIELD* TI
#614156 HYPERBILIVERDINEMIA; HBLVD
;;GREEN JAUNDICE
*FIELD* TX
A number sign (#) is used with this entry because hyperbiliverdinemia
read more(HBLVD) can be caused by heterozygous or homozygous mutation in the gene
encoding bilirubin reductase-alpha (BLVRA; 109750) on chromosome 7p13.
DESCRIPTION
Hyperbiliverdinemia can manifest as green jaundice, which is a green
discoloration of the skin, urine, serum, and other bodily fluids, due to
increased biliverdin resulting from inefficient conversion to bilirubin.
Although rarely reported, affected individuals appear to have symptoms
only in the context of obstructive cholestasis and/or liver failure. In
some cases, green jaundice can resolve after resolution of obstructive
cholestasis. Green jaundice has also been associated with malnutrition,
medication, and congenital biliary atresia (summary by Huffman et al.,
2009).
CLINICAL FEATURES
Gafvels et al. (2009) reported a 63-year-old Swedish man with alcoholic
liver failure and hyperbiliverdinemia manifested as green jaundice. The
patient first presented with fatigue, weight, loss, and nausea, and
laboratory studies showed elevated liver enzymes with normal serum
levels of bilirubin. He had a history of cholecystectomy and of heavy
alcohol consumption. He developed bleeding esophageal varices, ascites,
cirrhotic liver failure, and fatal encephalopathy. During the final
months of his life, he had green-tainted skin, sclerae, urine, and
ascitic fluid. Liquid chromatography and mass spectrometry identified
the green plasma and urine component as unconjugated biliverdin, which
was significantly increased compared to controls.
Nytofte et al. (2011) reported 2 unrelated Inuit women from Greenland
with episodic hyperbiliverdinemia and green jaundice. Both presented
with obstructive cholestasis due to multiple gallstones; 1 was pregnant
at the time. A green color developed in the skin, urine, serum, and
bile, and in the milk from the pregnant woman. Laboratory studies showed
increased liver enzymes and biliverdin in bodily fluids, but only 1 had
increased serum bilirubin. The green discoloration resolved in both
patients after surgical resolution of cholestasis. Nytofte et al. (2011)
concluded that biliary obstruction was the primary event, and green
jaundice appeared as a consequence.
MOLECULAR GENETICS
In a 63-year-old Swedish man with liver failure and hyperbiliverdinemia
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). Family study of 1 of the
women showed that each unaffected parent was heterozygous for the
mutation. The patient's 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. The findings indicated that
complete loss of BLVRA activity is a nonlethal condition.
*FIELD* RF
1. 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.
2. Huffman, C.; Chillag, S.; Paulman, L.; McMahon, C.: It's not easy
bein' green. Am. J. Med. 122: 820-822, 2009.
3. 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.
*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive
ABDOMEN:
[Liver];
Liver dysfunction;
[Biliary tract];
Cholestasis;
Cholelithiasis
SKIN, NAILS, HAIR:
[Skin];
Jaundice, green
LABORATORY ABNORMALITIES:
Green urine;
Green serum;
Increased biliverdin in bodily fluids;
Bilirubin may or may not be increased
MISCELLANEOUS:
Three patients have been reported (as of August 2011);
Green jaundice occurs only in the context of liver failure or obstructive
cholestasis;
Green color resolves if cholestasis is treated;
Both heterozygous and homozygous mutations have been reported
MOLECULAR BASIS:
Caused by mutation in the biliverdin reductase A gene (BLVRA, 109750.0001)
*FIELD* CD
Cassandra L. Kniffin: 8/9/2011
*FIELD* ED
joanna: 12/29/2011
ckniffin: 8/9/2011
*FIELD* CD
Cassandra L. Kniffin: 8/9/2011
*FIELD* ED
carol: 08/16/2011
wwang: 8/15/2011
ckniffin: 8/9/2011