RBCC

Full text data of CYB5R3

CYB5R3 (DIA1) [Confidence: high (present in two of the MS resources)]
NADH-cytochrome b5 reductase 3; B5R; Cytochrome b5 reductase; 1.6.2.2 (Diaphorase-1; NADH-cytochrome b5 reductase 3 membrane-bound form; NADH-cytochrome b5 reductase 3 soluble form)

hRBCD IPI00328415
IPI00328415 cytochrome b5 reductase membrane-bound isoform cytochrome b5 reductase membrane-bound isoform membrane n/a n/a 5 3 4 n/a 3 1 3 n/a 4 n/a 2 4 n/a n/a 2 2 2 n/a Membrane bound isoform n/a found at its expected molecular weight found at molecular weight

Comments
Isoform P00387-2 was detected.

UniProt P00387
ID NB5R3_HUMAN Reviewed; 301 AA.
AC P00387; B1AHF2; B7Z7L3; O75675; Q8TDL8; Q8WTS8; Q9UEN4; Q9UEN5;
read moreAC Q9UL55; Q9UL56;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 188.
DE RecName: Full=NADH-cytochrome b5 reductase 3;
DE Short=B5R;
DE Short=Cytochrome b5 reductase;
DE EC=1.6.2.2;
DE AltName: Full=Diaphorase-1;
DE Contains:
DE RecName: Full=NADH-cytochrome b5 reductase 3 membrane-bound form;
DE Contains:
DE RecName: Full=NADH-cytochrome b5 reductase 3 soluble form;
GN Name=CYB5R3; Synonyms=DIA1;
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 [GENOMIC DNA], AND VARIANT PRO-66.
RC TISSUE=Placenta;
RX PubMed=2479590; DOI=10.1016/0378-1119(89)90299-0;
RA Tomatsu S., Kobayashi Y., Fukumaki Y., Yubisui T., Orii T., Sakaki Y.;
RT "The organization and the complete nucleotide sequence of the human
RT NADH-cytochrome b5 reductase gene.";
RL Gene 80:353-361(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RA Voice M.W.;
RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Yoon B., Chung H., Ko E., Lee D.;
RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT PRO-66, AND VARIANTS
RP HM GLN-58; PRO-73 AND TYR-204.
RC TISSUE=Leukocyte;
RA Lan F.;
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-117.
RG NIEHS SNPs program;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Testis;
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 8-301 (ISOFORM 1), AND VARIANT PRO-66.
RC TISSUE=Liver;
RX PubMed=3035541; DOI=10.1073/pnas.84.11.3609;
RA Yubisui T., Naitoh Y., Zenno S., Tamura M., Takeshita M., Sakaki Y.;
RT "Molecular cloning of cDNAs of human liver and placenta NADH-
RT cytochrome b5 reductase.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:3609-3613(1987).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 101-250 (ISOFORM 1).
RA Diss J.K.J., Fraser S.P., Coombes R.C., Djamgoz M.B.A.;
RT "Upregulation of voltage-gated Na+ channel expression and metastatic
RT potential in human breast cancer: correlative studies on cell lines
RT and biopsy tissues.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP PROTEIN SEQUENCE OF 2-25, AND MYRISTOYLATION AT GLY-2.
RX PubMed=2498303;
RA Murakami K., Yubisui T., Takeshita M., Miyata T.;
RT "The NH2-terminal structures of human and rat liver microsomal NADH-
RT cytochrome b5 reductases.";
RL J. Biochem. 105:312-317(1989).
RN [14]
RP PROTEIN SEQUENCE OF 27-301.
RC TISSUE=Erythrocyte;
RX PubMed=3700359;
RA Yubisui T., Miyata T., Iwanaga S., Tamura M., Takeshita M.;
RT "Complete amino acid sequence of NADH-cytochrome b5 reductase purified
RT from human erythrocytes.";
RL J. Biochem. 99:407-422(1986).
RN [15]
RP PROTEIN SEQUENCE OF 27-301.
RC TISSUE=Erythrocyte;
RX PubMed=6389526;
RA Yubisui T., Miyata T., Iwanaga S., Tamura M., Yoshida S.,
RA Takeshita M., Nakajima H.;
RT "Amino acid sequence of NADH-cytochrome b5 reductase of human
RT erythrocytes.";
RL J. Biochem. 96:579-582(1984).
RN [16]
RP ALTERNATIVE PROMOTER USAGE.
RX PubMed=9639531;
RA Bulbarelli A., Valentini A., De Silvestris M., Cappellini M.D.,
RA Borgese N.;
RT "An erythroid-specific transcript generates the soluble form of NADH-
RT cytochrome b5 reductase in humans.";
RL Blood 92:310-319(1998).
RN [17]
RP MUTAGENESIS OF CYSTEINE RESIDUES.
RX PubMed=2019583;
RA Shirabe K., Yubisui T., Nishino T., Takeshita M.;
RT "Role of cysteine residues in human NADH-cytochrome b5 reductase
RT studied by site-directed mutagenesis. Cys-273 and Cys-283 are located
RT close to the NADH-binding site but are not catalytically essential.";
RL J. Biol. Chem. 266:7531-7536(1991).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-43, 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 [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-42, AND MASS 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 [20]
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 [21]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 31-301.
RX PubMed=15502298; DOI=10.1107/S0907444904020645;
RA Bando S., Takano T., Yubisui T., Shirabe K., Takeshita M.,
RA Nakagawa A.;
RT "Structure of human erythrocyte NADH-cytochrome b5 reductase.";
RL Acta Crystallogr. D 60:1929-1934(2004).
RN [22]
RP VARIANT METHB-CYB5R3 PRO-128.
RX PubMed=1898726;
RA Yubisui T., Shirabe K., Takeshita M., Kobayashi Y., Fukumaki Y.,
RA Sakaki Y., Takano T.;
RT "Structural role of serine 127 in the NADH-binding site of human NADH-
RT cytochrome b5 reductase.";
RL J. Biol. Chem. 266:66-70(1991).
RN [23]
RP VARIANTS METHB-CYB5R3 GLN-58 AND PRO-149.
RX PubMed=1707593;
RA Katsube T., Sakamoto N., Kobayashi Y., Seki R., Hirano M.,
RA Tanishima K., Tomoda A., Takazakura E., Yubisui T., Takeshita M.,
RA Sakaki Y., Fukumaki Y.;
RT "Exonic point mutations in NADH-cytochrome B5 reductase genes of
RT homozygotes for hereditary methemoglobinemia, types I and III:
RT putative mechanisms of tissue-dependent enzyme deficiency.";
RL Am. J. Hum. Genet. 48:799-808(1991).
RN [24]
RP VARIANT METHB-CYB5R3 MET-106.
RX PubMed=1400360;
RA Shirabe K., Yubisui T., Borgese N., Tang C.-Y., Hultquist D.E.,
RA Takeshita M.;
RT "Enzymatic instability of NADH-cytochrome b5 reductase as a cause of
RT hereditary methemoglobinemia type I (red cell type).";
RL J. Biol. Chem. 267:20416-20421(1992).
RN [25]
RP VARIANT METHB-CYB5R3 PHE-299 DEL.
RX PubMed=8119939;
RA Shirabe K., Fujimoto Y., Yubisui T., Takeshita M.;
RT "An in-frame deletion of codon 298 of the NADH-cytochrome b5 reductase
RT gene results in hereditary methemoglobinemia type II (generalized
RT type). A functional implication for the role of the COOH-terminal
RT region of the enzyme.";
RL J. Biol. Chem. 269:5952-5957(1994).
RN [26]
RP VARIANTS METHB-CYB5R3 ARG-204 AND MET-273 DEL.
RX PubMed=7718898;
RA Vieira L.M., Kaplan J.-C., Kahn A., Leroux A.;
RT "Four new mutations in the NADH-cytochrome b5 reductase gene from
RT patients with recessive congenital methemoglobinemia type II.";
RL Blood 85:2254-2262(1995).
RN [27]
RP VARIANT SER-117.
RX PubMed=9048929; DOI=10.1007/s004390050347;
RA Jenkins M.M., Prchal J.T.;
RT "A high-frequency polymorphism of NADH-cytochrome b5 reductase in
RT African-Americans.";
RL Hum. Genet. 99:248-250(1997).
RN [28]
RP VARIANT METHB-CYB5R3 PRO-73.
RX PubMed=9695975; DOI=10.1046/j.1365-2141.1998.00782.x;
RA Wu Y.-S., Huang C.-H., Wan Y., Huang Q.-J., Zhu Z.-Y.;
RT "Identification of a novel point mutation (Leu72-to-Pro) in the NADH-
RT cytochrome b5 reductase gene of a patient with hereditary
RT methaemoglobinaemia type I.";
RL Br. J. Haematol. 102:575-577(1998).
RN [29]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 76-83 AND 171-187, AND VARIANT
RP METHB-CYB5R3 VAL-179.
RX PubMed=9886302; DOI=10.1046/j.1365-2141.1998.01123.x;
RA Higasa K., Manabe J.I., Yubisui T., Sumimoto H., Pung-Amritt P.,
RA Tanphaichitr V.S., Fukumaki Y.;
RT "Molecular basis of hereditary methaemoglobinaemia, types I and II:
RT two novel mutations in the NADH-cytochrome b5 reductase gene.";
RL Br. J. Haematol. 103:922-930(1998).
RN [30]
RP VARIANT METHB-CYB5R3 TYR-204.
RX PubMed=10807796;
RA Wang Y., Wu Y.-S., Zheng P.-Z., Yang W.-X., Fang G.-A., Tang Y.-C.,
RA Xie F., Lan F.-H., Zhu Z.-Y.;
RT "A novel mutation in the NADH-cytochrome b5 reductase gene of a
RT Chinese patient with recessive congenital methemoglobinemia.";
RL Blood 95:3250-3255(2000).
RN [31]
RP VARIANT METHB-CYB5R3 GLN-58.
RX PubMed=15622768;
RA Huang C.-H., Xie Y., Wang Y., Wu Y.-S.;
RT "Arginine-glutamine replacement at residue 57 of NADH-cytochrome b5
RT reductase in Chinese hereditary methemoglobinemia.";
RL Zhonghua Xue Ye Xue Za Zhi 18:200-203(1997).
RN [32]
RP VARIANTS METHB-CYB5R3 GLU-256 DEL AND ASP-292.
RX PubMed=12393396; DOI=10.1182/blood-2002-05-1405;
RA Percy M.J., Gillespie M.J.S., Savage G., Hughes A.E., McMullin M.F.,
RA Lappin T.R.J.;
RT "Familial idiopathic methemoglobinemia revisited: original cases
RT reveal 2 novel mutations in NADH-cytochrome b5 reductase.";
RL Blood 100:3447-3449(2002).
RN [33]
RP CHARACTERIZATION OF VARIANTS METHB-CYB5R3 GLU-256 DEL AND ASP-292.
RX PubMed=15953014; DOI=10.1111/j.1365-2141.2005.05526.x;
RA Percy M.J., Crowley L.J., Davis C.A., McMullin M.F., Savage G.,
RA Hughes J., McMahon C., Quinn R.J.M., Smith O., Barber M.J.,
RA Lappin T.R.J.;
RT "Recessive congenital methaemoglobinaemia: functional characterization
RT of the novel D239G mutation in the NADH-binding lobe of cytochrome b5
RT reductase.";
RL Br. J. Haematol. 129:847-853(2005).
CC -!- FUNCTION: Desaturation and elongation of fatty acids, cholesterol
CC biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin
CC reduction.
CC -!- CATALYTIC ACTIVITY: NADH + 2 ferricytochrome b5 = NAD(+) + H(+) +
CC 2 ferrocytochrome b5.
CC -!- COFACTOR: FAD.
CC -!- SUBUNIT: Component of a complex composed of cytochrome b5, NADH-
CC cytochrome b5 reductase (CYB5R3) and MOSC2 (By similarity).
CC -!- SUBCELLULAR LOCATION: Isoform 1: Endoplasmic reticulum membrane;
CC Lipid-anchor; Cytoplasmic side. Mitochondrion outer membrane;
CC Lipid-anchor; Cytoplasmic side.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm. Note=Produces the
CC soluble form found in erythrocytes.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=M;
CC IsoId=P00387-1; Sequence=Displayed;
CC Name=2; Synonyms=S;
CC IsoId=P00387-2; Sequence=VSP_010200;
CC Name=3;
CC IsoId=P00387-3; Sequence=VSP_042827;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Isoform 2 is expressed at late stages of
CC erythroid maturation.
CC -!- POLYMORPHISM: Ser-117 seems to only be found in persons of African
CC origin. The allele frequency is 0.23 in African Americans. It was
CC not found in Caucasians, Asians, Indo-Aryans, or Arabs. There
CC seems to be no effect on the enzyme activity.
CC -!- DISEASE: Methemoglobinemia CYB5R3-related (METHB-CYB5R3)
CC [MIM:250800]: A form of methemoglobinemia, a hematologic disease
CC characterized by the presence of excessive amounts of
CC methemoglobin in blood cells, resulting in decreased oxygen
CC carrying capacity of the blood, cyanosis and hypoxia. There are
CC two types of methemoglobinemia CYB5R3-related. In type 1, the
CC defect affects the soluble form of the enzyme, is restricted to
CC red blood cells, and causes well-tolerated methemoglobinemia. In
CC type 2, the defect affects both the soluble and microsomal forms
CC of the enzyme and is thus generalized, affecting red cells,
CC leukocytes and all body tissues. Type 2 methemoglobinemia is
CC associated with mental deficiency and other neurologic symptoms.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the flavoprotein pyridine nucleotide
CC cytochrome reductase family.
CC -!- SIMILARITY: Contains 1 FAD-binding FR-type domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/dia1/";
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DR EMBL; M28713; AAA59900.1; -; Genomic_DNA.
DR EMBL; M28705; AAA59900.1; JOINED; Genomic_DNA.
DR EMBL; M28706; AAA59900.1; JOINED; Genomic_DNA.
DR EMBL; M28707; AAA59900.1; JOINED; Genomic_DNA.
DR EMBL; M28708; AAA59900.1; JOINED; Genomic_DNA.
DR EMBL; M28709; AAA59900.1; JOINED; Genomic_DNA.
DR EMBL; M28710; AAA59900.1; JOINED; Genomic_DNA.
DR EMBL; M28711; AAA59900.1; JOINED; Genomic_DNA.
DR EMBL; Y09501; CAA70696.1; -; mRNA.
DR EMBL; AF361370; AAL87744.1; -; mRNA.
DR EMBL; AJ010116; CAA09006.1; -; mRNA.
DR EMBL; AJ010117; CAA09007.1; -; mRNA.
DR EMBL; AJ010118; CAA09008.1; -; mRNA.
DR EMBL; AY341030; AAP88936.1; -; Genomic_DNA.
DR EMBL; BT009821; AAP88823.1; -; mRNA.
DR EMBL; CR456435; CAG30321.1; -; mRNA.
DR EMBL; AF061830; AAF06818.1; -; Genomic_DNA.
DR EMBL; AF061831; AAF06819.1; -; Genomic_DNA.
DR EMBL; AK302204; BAH13649.1; -; mRNA.
DR EMBL; Z93241; CAB42843.1; -; Genomic_DNA.
DR EMBL; Z93241; CAQ08414.1; -; Genomic_DNA.
DR EMBL; BC004821; AAH04821.1; -; mRNA.
DR EMBL; AJ310899; CAC84523.1; -; mRNA.
DR EMBL; AJ310900; CAC84524.1; -; mRNA.
DR EMBL; M16461; AAA52306.1; -; mRNA.
DR EMBL; M16462; AAA52307.1; -; mRNA.
DR PIR; JS0468; RDHUB5.
DR RefSeq; NP_000389.1; NM_000398.6.
DR RefSeq; NP_001123291.1; NM_001129819.2.
DR RefSeq; NP_001165131.1; NM_001171660.1.
DR RefSeq; NP_001165132.1; NM_001171661.1.
DR RefSeq; NP_015565.1; NM_007326.4.
DR UniGene; Hs.561064; -.
DR PDB; 1M91; Model; -; A=1-301.
DR PDB; 1UMK; X-ray; 1.75 A; A=27-301.
DR PDBsum; 1M91; -.
DR PDBsum; 1UMK; -.
DR ProteinModelPortal; P00387; -.
DR SMR; P00387; 31-301.
DR DIP; DIP-50463N; -.
DR IntAct; P00387; 2.
DR MINT; MINT-5003981; -.
DR ChEMBL; CHEMBL2146; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P00387; -.
DR DMDM; 127846; -.
DR REPRODUCTION-2DPAGE; IPI00446235; -.
DR PaxDb; P00387; -.
DR PRIDE; P00387; -.
DR DNASU; 1727; -.
DR Ensembl; ENST00000352397; ENSP00000338461; ENSG00000100243.
DR Ensembl; ENST00000361740; ENSP00000354468; ENSG00000100243.
DR Ensembl; ENST00000396303; ENSP00000379597; ENSG00000100243.
DR Ensembl; ENST00000402438; ENSP00000385679; ENSG00000100243.
DR Ensembl; ENST00000407332; ENSP00000384457; ENSG00000100243.
DR Ensembl; ENST00000407623; ENSP00000384834; ENSG00000100243.
DR GeneID; 1727; -.
DR KEGG; hsa:1727; -.
DR UCSC; uc003bcx.3; human.
DR CTD; 1727; -.
DR GeneCards; GC22M043014; -.
DR HGNC; HGNC:2873; CYB5R3.
DR HPA; HPA001566; -.
DR MIM; 250800; phenotype.
DR MIM; 613213; gene.
DR neXtProt; NX_P00387; -.
DR Orphanet; 139373; Recessive hereditary methemoglobinemia type 1.
DR Orphanet; 139380; Recessive hereditary methemoglobinemia type 2.
DR PharmGKB; PA27331; -.
DR eggNOG; COG0543; -.
DR HOGENOM; HOG000175005; -.
DR HOVERGEN; HBG052580; -.
DR InParanoid; P00387; -.
DR KO; K00326; -.
DR OMA; PPPMINA; -.
DR OrthoDB; EOG7CZK69; -.
DR PhylomeDB; P00387; -.
DR BioCyc; MetaCyc:HS02015-MONOMER; -.
DR BRENDA; 1.6.2.2; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; P00387; -.
DR EvolutionaryTrace; P00387; -.
DR GeneWiki; CYB5R3; -.
DR GenomeRNAi; 1727; -.
DR NextBio; 6983; -.
DR PRO; PR:P00387; -.
DR ArrayExpress; P00387; -.
DR Bgee; P00387; -.
DR CleanEx; HS_CYB5R3; -.
DR Genevestigator; P00387; -.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005833; C:hemoglobin complex; TAS:ProtInc.
DR GO; GO:0005811; C:lipid particle; IDA:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0043531; F:ADP binding; IEA:Ensembl.
DR GO; GO:0016208; F:AMP binding; IEA:Ensembl.
DR GO; GO:0004128; F:cytochrome-b5 reductase activity, acting on NAD(P)H; TAS:Reactome.
DR GO; GO:0071949; F:FAD binding; IDA:UniProtKB.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:Ensembl.
DR GO; GO:0051287; F:NAD binding; IEA:Ensembl.
DR GO; GO:0008015; P:blood circulation; TAS:ProtInc.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0019852; P:L-ascorbic acid metabolic process; TAS:Reactome.
DR InterPro; IPR017927; Fd_Rdtase_FAD-bd.
DR InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase.
DR InterPro; IPR001834; NADH-Cyt_B5_reductase.
DR InterPro; IPR008333; OxRdtase_FAD-bd_dom.
DR InterPro; IPR001433; OxRdtase_FAD/NAD-bd.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR Pfam; PF00970; FAD_binding_6; 1.
DR Pfam; PF00175; NAD_binding_1; 1.
DR PRINTS; PR00406; CYTB5RDTASE.
DR PRINTS; PR00371; FPNCR.
DR SUPFAM; SSF63380; SSF63380; 1.
DR PROSITE; PS51384; FAD_FR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative promoter usage;
KW Alternative splicing; Cholesterol biosynthesis;
KW Cholesterol metabolism; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Endoplasmic reticulum;
KW FAD; Flavoprotein; Lipid biosynthesis; Lipid metabolism; Lipoprotein;
KW Membrane; Mitochondrion; Mitochondrion outer membrane; Myristate; NAD;
KW Oxidoreductase; Phosphoprotein; Polymorphism; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 301 NADH-cytochrome b5 reductase 3 membrane-
FT bound form.
FT /FTId=PRO_0000019392.
FT CHAIN 27 301 NADH-cytochrome b5 reductase 3 soluble
FT form.
FT /FTId=PRO_0000019394.
FT DOMAIN 40 152 FAD-binding FR-type.
FT NP_BIND 132 147 FAD (By similarity).
FT NP_BIND 171 206 FAD (By similarity).
FT MOD_RES 42 42 N6-acetyllysine.
FT MOD_RES 43 43 Phosphotyrosine.
FT MOD_RES 120 120 N6-acetyllysine (By similarity).
FT LIPID 2 2 N-myristoyl glycine.
FT VAR_SEQ 1 23 Missing (in isoform 2).
FT /FTId=VSP_010200.
FT VAR_SEQ 1 7 MGAQLST -> MNRSLLVGCMQSKDIWGREESICERLKQDG
FT LDVERAESWE (in isoform 3).
FT /FTId=VSP_042827.
FT VARIANT 58 58 R -> Q (in METHB-CYB5R3; type 1; 62% of
FT activity).
FT /FTId=VAR_004619.
FT VARIANT 66 66 S -> P (in dbSNP:rs1130706).
FT /FTId=VAR_018419.
FT VARIANT 73 73 L -> P (in METHB-CYB5R3; type 1).
FT /FTId=VAR_010750.
FT VARIANT 106 106 V -> M (in METHB-CYB5R3; type 1; 77% of
FT activity; dbSNP:rs121965009).
FT /FTId=VAR_004620.
FT VARIANT 117 117 T -> S (in dbSNP:rs1800457).
FT /FTId=VAR_010751.
FT VARIANT 128 128 S -> P (in METHB-CYB5R3; type 2;
FT Hiroshima).
FT /FTId=VAR_004621.
FT VARIANT 149 149 L -> P (in METHB-CYB5R3).
FT /FTId=VAR_004622.
FT VARIANT 179 179 A -> V (in METHB-CYB5R3; type 1;
FT dbSNP:rs201232518).
FT /FTId=VAR_010752.
FT VARIANT 204 204 C -> R (in METHB-CYB5R3; type 2).
FT /FTId=VAR_010753.
FT VARIANT 204 204 C -> Y (in METHB-CYB5R3; type 1).
FT /FTId=VAR_010754.
FT VARIANT 256 256 Missing (in METHB-CYB5R3; type 1; retains
FT approximately 38% of residual diaphorase
FT activity).
FT /FTId=VAR_037315.
FT VARIANT 273 273 Missing (in METHB-CYB5R3; type 2).
FT /FTId=VAR_010755.
FT VARIANT 292 292 G -> D (in METHB-CYB5R3; type 1; retains
FT approximately 58% of residual diaphorase
FT activity).
FT /FTId=VAR_037316.
FT VARIANT 299 299 Missing (in METHB-CYB5R3; type2; almost
FT complete loss of activity).
FT /FTId=VAR_004623.
FT CONFLICT 28 32 QRSTP -> RWPRA (in Ref. 11; AAA52307).
FT CONFLICT 29 29 R -> G (in Ref. 1; AAA59900).
FT CONFLICT 31 31 T -> K (in Ref. 4; CAA09006/CAA09007/
FT CAA09008).
FT CONFLICT 34 35 IT -> LA (in Ref. 11; AAA52307).
FT CONFLICT 187 188 ML -> IV (in Ref. 4; CAA09006/CAA09007).
FT CONFLICT 191 192 IR -> MS (in Ref. 4; CAA09006/CAA09007).
FT CONFLICT 192 192 R -> G (in Ref. 11; AAA52306).
FT CONFLICT 233 234 FK -> CN (in Ref. 4; CAA09006/CAA09007).
FT CONFLICT 280 280 I -> N (in Ref. 3; AAL87744).
FT STRAND 43 52
FT STRAND 54 63
FT STRAND 78 85
FT STRAND 88 94
FT STRAND 104 111
FT STRAND 115 118
FT HELIX 126 133
FT STRAND 139 146
FT STRAND 148 153
FT STRAND 156 159
FT STRAND 168 171
FT STRAND 173 180
FT HELIX 181 183
FT HELIX 184 195
FT STRAND 203 212
FT HELIX 213 215
FT HELIX 219 228
FT TURN 230 232
FT STRAND 233 241
FT STRAND 247 252
FT HELIX 255 261
FT HELIX 265 267
FT STRAND 270 275
FT HELIX 277 282
FT HELIX 285 291
FT HELIX 295 297
FT STRAND 298 300
SQ SEQUENCE 301 AA; 34235 MW; FDCDCDC4EC3570B4 CRC64;
MGAQLSTLGH MVLFPVWFLY SLLMKLFQRS TPAITLESPD IKYPLRLIDR EIISHDTRRF
RFALPSPQHI LGLPVGQHIY LSARIDGNLV VRPYTPISSD DDKGFVDLVI KVYFKDTHPK
FPAGGKMSQY LESMQIGDTI EFRGPSGLLV YQGKGKFAIR PDKKSNPIIR TVKSVGMIAG
GTGITPMLQV IRAIMKDPDD HTVCHLLFAN QTEKDILLRP ELEELRNKHS ARFKLWYTLD
RAPEAWDYGQ GFVNEEMIRD HLPPPEEEPL VLMCGPPPMI QYACLPNLDH VGHPTERCFV
F
//

MIM 250800
*RECORD*
*FIELD* NO
250800
*FIELD* TI
#250800 METHEMOGLOBINEMIA DUE TO DEFICIENCY OF METHEMOGLOBIN REDUCTASE
;;NADH-DEPENDENT METHEMOGLOBIN REDUCTASE DEFICIENCY;;
read moreNADH-CYTOCHROME b5 REDUCTASE DEFICIENCY;;
METHEMOGLOBINEMIA, CONGENITAL, AUTOSOMAL RECESSIVE
METHEMOGLOBINEMIA, TYPE I, INCLUDED;;
METHEMOGLOBINEMIA, TYPE II, INCLUDED;;
NADH-CYTOCHROME b5 REDUCTASE DEFICIENCY, TYPE I, INCLUDED;;
NADH-CYTOCHROME b5 REDUCTASE DEFICIENCY, TYPE II, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
methemoglobinemia due to deficiency of methemoglobin reductase is caused
by mutation in the CYB5R3 gene (613213).

See also autosomal recessive methemoglobinemia type IV (250790), which
is caused by mutation in the cytochrome b5 gene (CYB5A; 613218). Type
III has been withdrawn (see below and Nagai et al., 1993).

Autosomal dominant methemoglobinemia, referred to as the 'M' type, is
caused by variation in the hemoglobin A (HBA1; 141800) or the hemoglobin
B (HBB; 141900) gene.

DESCRIPTION

Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an
autosomal recessive disorder characterized clinically by decreased
oxygen carrying capacity of the blood, with resultant cyanosis and
hypoxia (review by Percy and Lappin, 2008).

There are 2 types of methemoglobin reductase deficiency. In type I, the
defect affects the soluble form of the enzyme, is restricted to red
blood cells, and causes well-tolerated methemoglobinemia. In type II,
the defect affects both the soluble and microsomal forms of the enzyme
and is thus generalized, affecting red cells, leukocytes, and all body
tissues. Type II methemoglobinemia is associated with mental deficiency
and other neurologic symptoms. The neurologic symptoms may be related to
the major role played by the cytochrome b5 system in the desaturation of
fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979).

CLINICAL FEATURES

Gibson (1948) and Barcroft et al. (1945) correctly concluded that
erythrocytes from affected individuals with methemoglobinemia were
unable to reduce methemoglobin that is formed continuously at a normal
rate under physiologic conditions. Gibson (1948) is credited with
identifying this disorder as an enzymatic defect in a reductase (see
HISTORY below). Increased circulating levels of methemoglobin, which is
brown, give the skin a bluish color, which appears as cyanosis. In the
normal state, about 1% of hemoglobin exists as methemoglobin;
individuals become symptomatic when methemoglobin levels rise above 25%
(Jaffe, 1986). Vascular collapse, coma, and death can occur when
methemoglobin approaches 70% of total hemoglobin (review by Percy and
Lappin, 2008).

- Methemoglobinemia Type I

Tanishima et al. (1985) reported 2 Japanese brothers, born of
consanguineous parents, with hereditary methemoglobinemia due to
cytochrome b5 reductase deficiency. Katsube et al. (1991) provided
follow-up of this family. The brothers, who were 24 and 26 years old,
had moderate cyanosis without any evidence of neurologic involvement.
Initial laboratory studies (Tanishima et al., 1985) showed lack of
CYB5R3 enzyme activity in erythrocytes, leukocytes, and platelets.
However, enzyme activity was not deficient in nonhematopoietic cells.
Thus, the cases did not belong to either the classic erythrocytic or the
generalized type, and was tentatively designated 'type III.' A study of
relatives showed intermediate enzyme activity, consistent with
heterozygosity. Tanishima et al. (1985) concluded that diagnosis by
tissues other than blood cells may be important. Katsube et al. (1991)
identified a homozygous mutation in the CYB5R3 gene (L149P; 613213.0003)
in these patients. Further biochemical studies of these patients by
Nagai et al. (1993) revealed that they did have residual enzyme activity
in white blood cells, indicating that they actually had type I
methemoglobinemia. As this was the only family reported with
methemoglobinemia type III, that designation was shown not to exist.

Wu et al. (1998) reported a 3-year-old Chinese girl with type I
methemoglobinemia. The patient was born after normal pregnancy and
delivery. From the age of 1 month she appeared persistently cyanosed,
but without mental or neurologic abnormalities, and her respiratory and
cardiac functions were normal. The concentration of methemoglobin was
15%, and NADH-cytochrome b5R activity in erythrocytes was decreased. Her
5-year-old brother had the same symptoms, with 14.5% methemoglobin and
decreased b5R activity. The unaffected parents had heterozygous levels
of enzyme activity in red cells (about 65% of normal controls).

- Methemoglobinemia Type II

Mental deficiency occurs only with the generalized enzyme-deficient form
of the disorder, now known as type II (Hitzenberger, 1932;
Worster-Drought et al., 1953; Jaffe, 1963).

Leroux et al. (1975) reported methemoglobinemia and mental retardation
in patients with generalized deficiency of cytochrome b5 reductase.
Lawson et al. (1977) also concluded that low leukocyte diaphorase
correlates with mental retardation, a variable feature. The clinical
picture in the neurologic form was reviewed by Jaffe and Hsieh (1971).

Shirabe et al. (1995) reported a girl, born of Italian second-cousin
parents, with type II methemoglobinemia. She appeared cyanotic from the
first days of life. In addition, the first months of life were
characterized by feeding difficulties, failure to thrive, and
psychomotor developmental delay. Therapy with ascorbate did not improve
her neurologic condition. At 1 year of age, she had severe spastic and
dystonic quadriparesis with hyperkinetic involuntary movements, severe
microcephaly, and very simple and primitive reactions to environmental
changes. A few months later, she developed generalized tonic seizures
and myoclonic jerks that were not responsive to common antiepileptic
drugs. At the age of 9 years, the patient was in a vegetative status.
There was complete absence of immunologically detectable CYB5R3 enzyme
in blood cells and skin fibroblasts. Cultured fibroblasts of the patient
showed severely reduced NADH-dependent cytochrome c reductase,
ferricyanide reductase, and semidehydroascorbate reductase activities.

Vieira et al. (1995) reported an Algerian patient with methemoglobinemia
type II. The patient had profound mental retardation, microcephaly, and
bilateral athetosis associated with cyanosis and absent CYB5R3 enzyme
activities in erythrocytes, lymphocytes, and lymphoblastoid cell lines.
Genetic analysis identified a homozygous nonsense mutation in the CYB5R3
gene (R219X; 613213.0007).

Owen et al. (1997) reported a 4-year-old boy with type II
methemoglobinemia. He had dystonic athetoid cerebral palsy with mental
retardation and microcephaly. He was found to have 60% methemoglobinemia
that was persistent but responded to ascorbic acid treatment.

Aalfs et al. (2000) reported a child, born of healthy, unrelated
Hindustani Suriname parents, with type II methemoglobinemia. She was
born small for gestational age. Central cyanosis was noted shortly after
birth. She had severe psychomotor retardation and microcephaly.
Neurologic features included athetoid movements, generalized hypertonia,
epilepsy, and a complete head lag. At 6 years of age, MRI of the brain
demonstrated frontal and bitemporal cortical atrophy, cerebellar
atrophy, retarded myelinization, and hypoplasia of the basal ganglia.
There was almost no psychomotor development and she developed spastic
tetraplegia with scoliosis. The patient died at the age of 8 years.
Genetic analysis identified compound heterozygosity for 2 nonsense
mutations in the CYB5R3 gene (Q77X; 613213.0014 and R160X; 613213.0015).

- Enterogenous Methemoglobinemia

Neonates have only about 60% of normal adult levels of CYB5R3 and do not
attain mature levels before 2 months of age (Wright et al., 1999).
Low-birth-weight neonates have low levels of erythrocyte CYB5R3
(Miyazono et al., 1999). Thus, even infants without CYB5R3 mutations are
at risk of developing methemoglobinemia if exposed to strong oxidizing
agents, such as drugs.

Enterogenous methemoglobinemia might be confused with the genetic form.
Rossi et al. (1966) described a patient with chronic methemoglobinemia
for 14 years whose disorder was resolved by a course of neomycin.

Cohen et al. (1968) suggested that methemoglobinemia induced by malarial
prophylaxis, such as chloroquine, primaquine and
diamino-diphenylsulfone, could be an indication of the presence of the
heterozygous state. In a historic article, Comly (1945) reported
cyanosis in infants caused by nitrates in well water, which could easily
be confused with cyanotic congenital heart disease and at times He could
be fatal (Johnson et al., 1987). This continues to be a problem in rural
areas. Presumably, an infant with methemoglobin reductase deficiency,
and possibly even a heterozygote, would be unusually vulnerable.

Maran et al. (2005) reported 3 unrelated patients with acquired
methemoglobinemia and no mutations in the CYB5R3 gene. One was an infant
with age-related decreased CYB5R3 activity (60%) and 35% methemoglobin.
The infant had 1 week of a diarrheal illness and required several
administrations of methylene blue. Another patient developed
methemoglobinemia upon exposure to lidocaine, and the third patient, who
had 44% methemoglobin, had an unidentified toxin or infection.

BIOCHEMICAL FEATURES

West et al. (1967) provided electrophoretic evidence of anomalous enzyme
structure of NADH diaphorase (the former name of CYB5R3; Percy and
Lappin, 2008) in a case of methemoglobinemia. West et al. (1967) noted
that electrophoretic variants of NADH diaphorase without
methemoglobinemia have also been found, with a family pattern consistent
with codominant inheritance.

By electrophoresis, Bloom and Zarkowsky (1969) described 3 varieties of
the NADH diaphorase enzyme in patients with methemoglobinemia: total
absence of detectable enzyme activity, decreased quantities of
presumably normal enzyme, and decreased quantities of structurally
variant enzyme. They added 2 new structural variants of
NADH-methemoglobin reductase to the one originally described by Kaplan
and Beutler (1967).

DIAGNOSIS

- Prenatal Diagnosis

Kaftory et al. (1986) made the prenatal diagnosis of congenital
methemoglobinemia with mental retardation by demonstration of an almost
complete deficiency of cytochrome b5 reductase activity in cultured
amniotic fluid cells.

CLINICAL MANAGEMENT

Treatment with methylene blue (100-300 mg orally per day) or ascorbic
acid (500 mg a day) is of cosmetic value (Waller, 1970). Methylene blue
stimulates production of reduced NADPH through the pentose phosphate
pathway in red blood cells (Percy and Lappin, 2008).

Karadsheh et al. (2001) reported a patient with coexisting
glucose-6-phosphate deficiency (300908) and CYB5R3 deficiency. He
developed metoclopramide-induced methemoglobinemia that did not respond
to methylene blue treatment. This was because G6PD patients have
blockage of the pentose phosphate pathway, which generates NADPH.

MOLECULAR GENETICS

In a 3-year-old Chinese girl with type I methemoglobinemia, Wu et al.
(1998) identified a homozygous mutation in the CYB5R3 gene (L73P;
613213.0013).

In an Italian girl with severe type II methemoglobinemia, Shirabe et al.
(1995) identified a homozygous mutation in the CYB5R3 gene
(613213.0005).

In a 4-year-old boy with type II methemoglobinemia, Owen et al. (1997)
identified a homozygous splice site mutation in the CYB5R3 gene that
resulted in the deletion of exon 6 (613213.0012).

Maran et al. (2005) reported 4 unrelated patients with recessive
methemoglobinemia: 2 with type I and 2 with type II. Four different
mutations in the CYB5R3 gene were identified (see, e.g., 613213.0008 and
613218.0012).

POPULATION GENETICS

The enzymatic type of methemoglobinemia has unprecedentedly high
frequency in the Athabaskan Indians (Eskimos) of Alaska (Scott, 1960;
Scott et al., 1963). Balsamo et al. (1964) also observed CYB5R3
deficiency in Navajo Indians. Since the Navajo Indians and the
Athabaskan Indians of Alaska are the same linguistic stock, the finding
may illustrate the usefulness of rare recessive genes in tracing
relationships of ethnic groups.

Following up on an observation of an unusually high proportion of
Algerian subjects among patients with methemoglobinemia, Reghis et al.
(1981) did a population survey of red cell cytochrome b5 reductase in
1,000 Algerian subjects. In 16, the activity of the enzyme was
diminished by about 50%. The relatively high frequency of the deficiency
allele was found in subjects of Kabyle origin.

NOMENCLATURE

Jaffe (1987) stated that the enzyme can be called cytochrome b5
reductase (dropping the NADH prefix) and the disorder can be called
'enzymopenic methemoglobinemia.'

HISTORY

Methemoglobinemia, although not usually considered an inborn error of
metabolism in the strict garrodian sense, was the first hereditary trait
in which a specific enzyme deficiency was identified (Gibson, 1948).
(Type I glycogen storage disease (232200) is usually listed as the first
disorder in which a specific enzymopathy was identified, by Cori and
Cori, 1952).

Gibson (1993) gave a delightful account of his work on the enzyme defect
in methemoglobinemia in Belfast, Northern Ireland. The patients he
studied were 2 brothers, Russell and Fred Martin from Banbridge in
Northern Ireland, in whom Dr. James Deeny, a local practitioner with
early enthusiasm for ascorbic acid in the treatment of heart disease,
had demonstrated the benefit of vitamin C (Deeny et al., 1943). The
brothers had a blue appearance. When Russell was treated with vitamin C,
he turned pink. Although Deeny assumed that he had corrected an
underlying heart condition, cardiologists could find no cardiac
abnormality in either brother. The physiologist Henry Barcroft carried
out a detailed study of these cases during treatment and found raised
levels of methemoglobin (Barcroft et al., 1945). Quentin Gibson (then of
Queen's University, Belfast, Ireland) correctly identified the pathway
involved in the reduction of methemoglobin in the family, thereby
describing the first hereditary trait involving a specific enzyme
deficiency (Gibson, 1948). See also the personal account of Gibson
(2002).

Trost (1982) gave a popular account of the 'blue Fugates' of Kentucky
and the studies of them by Cawein et al. (1964).

- Early Reports of Possible Other Defects Causing Methemoglobinemia

Townes and Morrison (1962) reported biochemical studies of a variant of
autosomal recessive methemoglobinemia. NADH-methemoglobin reductase
(CYB5R3) activity of red cells was in the normal range and hemoglobin
was apparently normal. Methemoglobin reduction in intact red cells was
very low with glucose as the substrate, but normal with lactate.
Intracellular glutathione was also low. Townes and Morrison (1962)
postulated that the defect might be inadequate NADH formation resulting
from decreased glutathione synthesis. However, this may have represented
a basically different form of methemoglobinemia.

Muller et al. (1963) described 3 sibs with methemoglobinemia. Laboratory
studies showed a deficient ability of erythrocytes to utilize glucose
for methemoglobin reduction, but normal reduction of lactate. They
suggested that their family had a hereditary deficiency of NADPH
methaemoglobin reductase (CYB5R4; 608343). A deficiency of NADPH has
never been reported.

Ozsoylu (1967) reported enzyme-deficiency methemoglobinemia in 3
generations and proposed dominant inheritance. However, consanguinity
was present to account for a quasi-dominant pattern. The author thought
this possibility was excluded by normal enzyme activity in individuals
who would need to be heterozygotes to account for the pattern.

*FIELD* SA
Board and Pidcock (1981); Choury et al. (1981); Fialkow et al. (1965);
Gonzalez et al. (1978); Hirano et al. (1981); Hsieh and Jaffe (1971);
Junien et al. (1981); Lostanlen et al. (1981); Reghis et al. (1983);
Schwartz et al. (1972); Tanishima et al. (1980)
*FIELD* RF
1. Aalfs, C. M.; Salieb-Beugelaar, G. B.; Wanders, R. J. A.; Mannens,
M. M. A. M.; Wijburg, F. A.: A case of methemoglobinemia type II
due to NADH-cytochrome b5 reductase deficiency: determination of the
molecular basis. Hum. Mutat. 16: 18-22, 2000.

2. Balsamo, P.; Hardy, W. R.; Scott, E. M.: Hereditary methemoglobinemia
due to diaphorase deficiency in Navajo Indians. J. Pediat. 65: 928-930,
1964.

3. Barcroft, H.; Gibson, Q. H.; Harrison, D. C.; McMurray, J.: Familial
idiopathic methaemoglobinaemia and its treatment with ascorbic acid. Clin.
Sci. 5: 145-157, 1945.

4. Bloom, G. E.; Zarkowsky, H. S.: Heterogeneity of the enzyme defect
in congenital methemoglobinemia. New Eng. J. Med. 281: 919-922,
1969.

5. Board, P. G.; Pidcock, M. E.: Methaemoglobinaemia resulting from
heterozygosity for two NADH-methaemoglobin reductase variants: characterization
as NADH-ferricyanide reductase. Brit. J. Haemat. 47: 361-370, 1981.

6. Cawein, M. J.; Behlen, C. H.; Lappat, E. J.; Cohn, J. E.: Hereditary
diaphorase deficiency and methemoglobinemia. Arch. Intern. Med. 113:
578-585, 1964.

7. Choury, D.; Leroux, A.; Kaplan, J.-C.: Membrane-bound cytochrome
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8. Cohen, R. J.; Sachs, J. R.; Wicker, D. J.; Conrad, M. E.: Methemoglobinemia
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9. Comly, H. H.: Cyanosis in infants caused by nitrates in well water. JAMA 129:
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10. Cori, G. T.; Cori, C. F.: Glucose-6-phosphatase of the liver
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11. Deeny, J.; Murdock, E. T.; Rogan, J. J.: Familial idiopathic
methaemoglobinaemia with a note on the treatment of two cases with
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12. Fialkow, P. J.; Browder, J. A.; Sparkes, R. S.; Motulsky, A. G.
: Mental retardation in methemoglobinemia due to diaphorase deficiency. New
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13. Gibson, Q.: Introduction: congenital methemoglobinemia revisited.
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14. Gibson, Q. H.: Methemoglobinemia--long ago and far away. Am.
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15. Gibson, Q. H.: The reduction of methaemoglobin in red blood cells
and studies on the cause of idiopathic methaemoglobinaemia. Biochem.
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16. Gonzalez, R.; Estrada, M.; Wade, M.; de la Torre, E.; Svarch,
E.; Fernandez, O.; Oritz, R.; Guzman, E.; Colombo, B.: Heterogeneity
of hereditary methaemoglobinaemia: a study of 4 Cuban families with
NADH-methaemoglobin reductase deficiency including a new variant (Santiage
de Cuba variant). Scand. J. Haemat. 20: 385-393, 1978.

17. Hirano, M.; Matsuki, T.; Tanishima, K.; Takeshita, M.; Shimizu,
S.; Nagamura, Y.; Yoneyama, Y.: Congenital methaemoglobinaemia due
to NADH methaemoglobin reductase deficiency: successful treatment
with oral riboflavin. Brit. J. Haemat. 47: 353-359, 1981.

18. Hitzenberger, K.: Autotoxic cyanosis due to intraglobular methemoglobinemia. Wien.
Arch. Med. 23: 85-96, 1932.

19. Hsieh, H.-S.; Jaffe, E. R.: Electrophoretic and functional variants
of NADH-methemoglobin reductase in hereditary methemoglobinemia. J.
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20. Jaffe, E. R.: The reduction of methemoglobin in erythrocytes
of a patient with congenital methemoglobinemia, subjects with erythrocyte
glucose-6-phosphate dehydrogenase deficiency, and normal individuals. Blood 21:
561-572, 1963.

21. Jaffe, E. R.: Enzymopenic hereditary methemoglobinemia: a clinical/biochemical
classification. Blood Cells 12: 81-90, 1986.

22. Jaffe, E. R.: Personal Communication. Bronx, N. Y. 8/5/1987.

23. Jaffe, E. R.; Hsieh, H. S.: DPNH-methemoglobin reductase deficiency
and hereditary methemoglobinemia. Seminars Hemat. 8: 417-437, 1971.

24. Johnson, C. J.; Bonrud, P. A.; Dosch, T. L.; Kilness, A. W.; Senger,
K. A.; Busch, D. C.; Meyer, M. R.: Fatal outcome of methemoglobinemia
in an infant. JAMA 257: 2796-2797, 1987.

25. Junien, C.; Leroux, A.; Lostanlen, D.; Reghis, A.; Boue, J.; Nicolas,
H.; Boue, A.; Kaplan, J. C.: Prenatal diagnosis of congenital enzymopenic
methaemoglobinaemia with mental retardation due to generalized cytochrome
b5 reductase deficiency: first report of two cases. Prenatal Diag. 1:
17-24, 1981.

26. Kaftory, A.; Freundlich, E.; Manaster, J.; Shukri, A.; Hegesh,
E.: Prenatal diagnosis of congenital methemoglobinemia with mental
retardation. Isr. J. Med. Sci. 22: 837-840, 1986.

27. Kaplan, J. C.; Beutler, E.: Electrophoresis of red cell NADH-
and NADPH-diaphorases in normal subjects and patients with congenital
methemoglobinemia. Biochem. Biophys. Res. Commun. 29: 605-610, 1967.

28. Kaplan, J. C.; Leroux, A.; Beauvais, P.: Formes cliniques et
biologiques du deficit en cytochrome b5 reductase. Comp. Rend. Soc.
Biol. 173: 368-379, 1979.

29. Karadsheh, N. S.; Shaker, Q.; Ratroat, B.: Metoclopramide-induced
methemoglobinemia in a patient with co-existing deficiency of glucose-6-phosphate
dehydrogenase and NADH-cytochrome b5 reductase: failure of methylene
blue treatment. (Letter) Haematologica 86: 659 only, 2001.

30. Katsube, T.; Sakamoto, N.; Kobayashi, Y.; Seki, R.; Hirano, M.;
Tanishima, K.; Tomoda, A.; Takazakura, E.; Yubisui, T.; Takeshita,
M.; Sakaki, Y.; Fukumaki, Y.: Exonic point mutations in NADH-cytochrome
B5 reductase genes of homozygotes for hereditary methemoglobinemia,
types I and III: putative mechanisms of tissue-dependent enzyme deficiency. Am.
J. Hum. Genet. 48: 799-808, 1991.

31. Lawson, D. L.; Miale, T. D.; Harvey, J. L.; Bucciarelli, R. L.;
Nelson, L. S.: Leukocyte diaphorase deficiency in congenital methemoglobinemia:
a valuable prognostic indicator. Biol. Neonate 32: 193-196, 1977.

32. Leroux, A.; Junien, C.; Kaplan, J.-C.; Bamberger, J.: Generalised
deficiency of cytochrome b5 reductase in congenital methaemoglobinaemia
with mental retardation. Nature 258: 619-620, 1975.

33. Lostanlen, D.; Lenoir, G.; Kaplan, J.-C.: NADH-cytochrome b5
reductase activity in lymphoid cell lines: expression of the defect
in Epstein-Barr virus transformed lymphoblastoid cell lines from patients
with recessive congenital methemoglobinemia. J. Clin. Invest. 68:
279-285, 1981.

34. Maran, J.; Guan, Y.; Ou, C.-N.; Prchal, J. T.: Heterogeneity
of the molecular biology of methemoglobinemia: a study of eight consecutive
patients. (Letter) Haematologica 90: 687-689, 2005.

35. Miyazono, Y.; Hirono, A.; Miyamoto, Y.; Miwa, S.: Erythrocyte
enzyme activities in cord blood of extremely low-birth-weight infants. Am.
J. Hemat. 62: 88-92, 1999.

36. Muller, J.; Murawski, K.; Szymanowska, Z.; Koziorowski, A.; Radwan,
L.: Hereditary deficiency of NADPH 2-methaemoglobin reductase. Acta
Med. Scand. 173: 243-247, 1963.

37. Nagai, T.; Shirabe, K.; Yubisui, T.; Takeshita, M.: Analysis
of mutant NADH-cytochrome b5 reductase: apparent 'type III' methemoglobinemia
can be explained as type I with an unstable reductase. Blood 81:
808-814, 1993.

38. Owen, E. P.; Berens, J.; Marinaki, A. M.; Ipp, H.; Harley, E.
H.: Recessive congenital methaemoglobinaemia type II, a new mutation
which causes incorrect splicing in the NADH-cytochrome b-5 reductase
gene. J. Inherit. Metab. Dis. 20: 610 only, 1997.

39. Ozsoylu, S.: Hereditary methemoglobinemic cyanosis due to diaphorase
deficiency in three successive generations. Acta Haemat. 37: 276-283,
1967.

40. Percy, M. J.; Lappin, T. R.: Recessive congenital methaemoglobinaemia:
cytochrome b5 reductase deficiency. Brit. J. Haematol. 141: 298-308,
2008.

41. Reghis, A.; Benabadji, M.; Tchen, P.; Kaplan, J. C.: Quantitative
variations of red-cell cytochrome b5 reductase (NADH-methemoglobin-reductase)
in the Algerian population: evidence for defective alleles. Hum.
Genet. 59: 148-153, 1981.

42. Reghis, A.; Troungos, C.; Lostanlen, D.; Krishnamoorthy, R.; Kaplan,
J. C.: Characterization of weak alleles at the DIA1 locus (Mustapha
1, Mustapha 2, and Mustapha 3) in the Algerian population. Hum. Genet. 64:
173-175, 1983.

43. Rossi, E. C.; Bryan, G. T.; Schilling, R. F.; Clatanoff, D. V.
: Remission of chronic methemoglobinemia following neomycin therapy. Am.
J. Med. 40: 440-447, 1966.

44. Schwartz, J. M.; Paress, P. S.; Ross, J. M.; Dipillo, F.; Rizek,
R.: Unstable variant of NADH methemoglobin reductase in Puerto Ricans
with hereditary methemoglobinemia. J. Clin. Invest. 51: 1594-1601,
1972.

45. Scott, E. M.: The relationship of diaphorase of human erythrocytes
to inheritance of methemoglobinemia. J. Clin. Invest. 39: 1176-1179,
1960.

46. Scott, E. M.; Lewis, M.; Kaita, H.; Chown, B.; Giblett, E. R.
: The absence of close linkage of methemoglobinemia and blood group
loci. Am. J. Hum. Genet. 15: 493-494, 1963.

47. Shirabe, K.; Landi, M. T.; Takeshita, M.; Uziel, G.; Fedrizzi,
E.; Borgese, N.: A novel point mutation in a 3-prime splice site
of the NADH-cytochrome b5 reductase gene results in immunologically
undetectable enzyme and impaired NADH-dependent ascorbate regeneration
in cultured fibroblasts of a patient with type II hereditary methemoglobinemia. Am.
J. Hum. Genet. 57: 302-310, 1995.

48. Tanishima, K.; Matsuki, T.; Fukuda, N.; Takeshita, M.; Yoneyama,
Y.: NADH-cytochrome b5 reductase in platelets and leukocytes with
special reference to normal levels and to levels in carriers of hereditary
methemoglobinemia with or without neurological symptoms. Acta Haemat. 63:
7-12, 1980.

49. Tanishima, K.; Tanimoto, K.; Tomoda, A.; Mawatari, K.; Matsukawa,
S.; Yoneyama, Y.; Ohkuwa, H.; Takazakura, E.: Hereditary methemoglobinemia
due to cytochrome b(5) reductase deficiency in blood cells without
associated neurologic and mental disorders. Blood 66: 1288-1291,
1985.

50. Townes, P. L.; Morrison, M.: Investigation of the defect in a
variant of hereditary methemoglobinemia. Blood 19: 60-74, 1962.

51. Trost, C.: The Blue People of Troublesome Creek. Science 82
(Nov.): 35-39, 1982.

52. Vieira, L. M.; Kaplan, J.-C.; Kahn, A.; Leroux, A.: Four new
mutations in the NADH-cytochrome b5 reductase gene from patients with
recessive congenital methemoglobinemia type II. Blood 85: 2254-2262,
1995.

53. Vives-Corrons, J. L.; Pujades, A.; Vela, E.; Corretger, J. M.;
Leroux, A.; Kaplan, J. C.: Congenital methemoglobin-reductase (cytochrome
b5 reductase) deficiency associated with mental retardation in a Spanish
girl. Acta Haemat. 59: 348-353, 1978.

54. Waller, H. D.: Inherited methemoglobinemia (enzyme deficiencies). Humangenetik 9:
217-218, 1970.

55. West, C. A.; Gomperts, B. D.; Huehns, E. R.; Kessel, I.; Ashby,
J. R.: Demonstration of an enzyme variant in a case of congenital
methaemoglobinaemia. Brit. Med. J. 4: 212-214, 1967.

56. Worster-Drought, C.; White, J. C.; Sargent, F.: Familial, idiopathic
methaemoglobinaemia associated with mental deficiency and neurological
abnormalities. Brit. Med. J. 2: 114-118, 1953.

57. Wright, R. O.; Lewander, W. J.; Woolf, A. D.: Methemoglobinemia:
etiology, pharmacology, and clinical management. Ann. Emerg. Med. 34:
646-656, 1999.

58. Wu, Y.-S.; Huang, C.-H.; Wan, Y.; Huang, Q.-J.; Zhu, Z.-Y.: Identification
of a novel point mutation (leu72-to-pro) in the NADH-cytochrome b5
reductase gene of a patient with hereditary methaemoglobinaemia type
I. Brit. J. Haemat. 102: 575-577, 1998.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Growth retardation

HEAD AND NECK:
[Head];
Microcephaly (type II);
[Eyes];
Strabismus (type II)

RESPIRATORY:
Dyspnea, exertional

SKIN, NAILS, HAIR:
[Skin];
Cyanosis

NEUROLOGIC:
[Central nervous system];
Headache;
Mental retardation (type I);
Developmental delay (type II);
Opisthotonos (type II);
Hypertonia (type II);
Spasticity (type II);
Myelination defects (type II)

HEMATOLOGY:
Polycythemia;
Type I - methemoglobin concentration 10-35%

LABORATORY ABNORMALITIES:
NADH-cytochrome b(5) reductase deficiency

MISCELLANEOUS:
Most common form of congenital methemoglobinemia;
Two clinical forms - type I (deficiency of b5R is isolated to erythrocytes)
and type II (deficiency of b5R in all cell types);
Type II is progressive and leads to shortened lifespan;
Type I b5R endemic in Athabascan Indians, Navajo Indians, and Yakutsk
natives of Siberia;
Heterozygotes at risk of developing acute, symptomatic methemoglobinemia
after exposure to exogenous, methemoglobin-inducing agents

MOLECULAR BASIS:
Caused by mutation in the cytochrome b5 reductase 3 gene (CYB5R3,
613213.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 1/13/2010
Kelly A. Przylepa - revised: 8/13/2001

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/19/2011
ckniffin: 1/13/2010
alopez: 3/28/2006
joanna: 12/4/2002
joanna: 8/13/2001

*FIELD* CN
Cassandra L. Kniffin - reorganized: 1/20/2010
Cassandra L. Kniffin - updated: 1/13/2010
Cassandra L. Kniffin - updated: 10/17/2005
Victor A. McKusick - updated: 1/27/2003
Victor A. McKusick - updated: 4/3/2001
Victor A. McKusick - updated: 8/24/2000
Victor A. McKusick - updated: 8/17/2000
Victor A. McKusick - updated: 3/11/1999
Victor A. McKusick - updated: 2/12/1998
Victor A. McKusick - updated: 12/10/1997
Mark H. Paalman - updated: 4/17/1997
Victor A. McKusick - updated: 2/17/1997
Stylianos E. Antonarakis - updated: 7/4/1996

*FIELD* CD
Victor A. McKusick: 6/24/1986

*FIELD* ED
carol: 10/24/2013
terry: 10/12/2010
ckniffin: 4/8/2010
carol: 4/8/2010
carol: 2/24/2010
carol: 2/22/2010
carol: 1/20/2010
ckniffin: 1/13/2010
joanna: 9/4/2009
terry: 6/3/2009
carol: 3/20/2009
terry: 11/15/2006
wwang: 10/26/2005
ckniffin: 10/17/2005
wwang: 4/8/2005
carol: 3/17/2004
mgross: 12/16/2003
ckniffin: 7/8/2003
carol: 6/10/2003
terry: 5/16/2003
ckniffin: 2/28/2003
cwells: 1/27/2003
tkritzer: 1/21/2003
carol: 3/29/2002
terry: 6/6/2001
cwells: 4/9/2001
cwells: 4/4/2001
mcapotos: 4/3/2001
mcapotos: 8/30/2000
mcapotos: 8/29/2000
carol: 8/28/2000
terry: 8/24/2000
carol: 8/18/2000
terry: 8/17/2000
carol: 3/16/1999
terry: 3/11/1999
carol: 7/30/1998
terry: 6/4/1998
mark: 2/18/1998
terry: 2/12/1998
mark: 12/17/1997
terry: 12/10/1997
alopez: 4/17/1997
mark: 4/17/1997
mark: 2/17/1997
terry: 2/11/1997
carol: 7/4/1996
terry: 7/1/1996
mark: 9/13/1995
davew: 7/26/1994
carol: 4/20/1994
mimadm: 4/18/1994
warfield: 4/15/1994
carol: 5/13/1993

MIM 613213
*RECORD*
*FIELD* NO
613213
*FIELD* TI
*613213 CYTOCHROME b5 REDUCTASE 3; CYB5R3
;;B5R;;
NADH-DIAPHORASE 1; DIA1
*FIELD* TX
read more
DESCRIPTION

The CYB5R3 gene encodes cytochrome b5 reductase-3 (EC 1.6.2.2.), an
enzyme that catalyzes the transfer of reducing equivalents from NADH to
cytochrome b5 (CYB5A; 613218), which then acts as an electron donor. The
membrane-bound isoform of CYB5R3 plays a role in physiologic processes,
including cholesterol biosynthesis and fatty acid elongation and
desaturation, whereas the soluble isoform of CYB5R3 is present in
erythrocytes and functions to reduce methemoglobin to hemoglobin (review
by Percy and Lappin, 2008).

CLONING

Yubisui et al. (1987) reported molecular cloning of cDNAs for the gene
mutant in autosomal recessive methemoglobinemia (250800). There are 2
forms of NADH-cytochrome b5 reductase: a membrane-bound form in somatic
cells and a soluble form in erythrocytes. The former exists mainly on
the cytoplasmic side of the endoplasmic reticulum and functions in
desaturation and elongation of fatty acids, in cholesterol biosynthesis,
and in drug metabolism. The erythrocyte form is located in a soluble
fraction of circulating erythrocytes and is involved in methemoglobin
reduction. Membrane-bound enzyme consists of 300 amino acid residues
having both membrane-binding and catalytic domains. The soluble type
consists of 275 amino acids having only the catalytic domain. The 2
forms of the enzyme are coded by the same gene, CYB5R3 (Katsube et al.,
1991).

Pietrini et al. (1992) showed that the 2 forms of NADH-cytochrome b5
reductase are produced from a single gene: a myristylated membrane-bound
enzyme expressed in all tissues, and a soluble, erythrocyte-specific
isoform. The 2 forms are identical except for the N terminus, which
mediates binding to the lipid bilayer in the membrane and contains the
myristylation consensus sequence. They are produced by the use of
alternative promoter/alternate exons: the ubiquitous transcript is
generated from an upstream housekeeping promoter, while the reticulocyte
transcript originates from a downstream, erythroid-specific promoter.

Several workers suggested that the human soluble form is generated
through posttranslational processing of the membrane-bound form. Du et
al. (1997) used 5-prime-rapid amplification of cDNA ends (RACE) for
human reticulocyte, liver, brain, and HL-60 cell mRNAs to demonstrate
the ubiquitous presence of an alternative type of human b5R mRNA that
can probably be translated into the soluble form directly; however, the
erythroid-specific transcript of the b5R gene was not found. They showed
that this type of b5R mRNA, initiating from at least 2 sites, contains a
noncoding new first exon located between the first 2 exons of the human
b5R gene previously identified. In addition, this new first exon shares
62% homology with the rat erythroid-specific exon, whereas the 5-prime
flanking region of the new first exon possesses features of a
housekeeping gene.

GENE STRUCTURE

Tomatsu et al. (1989) demonstrated that the CYB5R3 gene is about 31 kb
long and contains 9 exons.

GENE FUNCTION

Straub et al. (2012) reported a new model for the regulation of nitric
oxide (NO) signaling by demonstrating that hemoglobin alpha, encoded by
the HBA1 (141800) and HBA2 (141850) genes, is expressed in human and
mouse arterial endothelial cells and enriched at the myoendothelial
junction, where it regulates the effects of NO on vascular reactivity.
Notably, this function is unique to hemoglobin alpha and is abrogated by
its genetic depletion. Mechanistically, endothelial hemoglobin alpha
heme iron in the Fe(3+) state permits NO signaling, and this signaling
is shut off when hemoglobin alpha is reduced to the Fe(2+) state by
endothelial CYB5R3. Genetic and pharmacologic inhibition of CYB5R3
increased NO bioactivity in small arteries. Straub et al. (2012)
concluded that their data revealed a mechanism by which the regulation
of the intracellular hemoglobin alpha oxidation state controls nitric
oxide synthase (NOS; see 163729) signaling in nonerythroid cells. The
authors suggested that this model may be relevant to heme-containing
globins in a broad range of NOS-containing somatic cells.

MAPPING

By study of rodent-human hybrids, Fisher et al. (1977) demonstrated that
the locus for NADH-diaphorase-1 (methemoglobin reductase; cytochrome b5
reductase) is on chromosome 22.

Bull et al. (1988) mapped the CYB5R3 gene to chromosome 22 by somatic
cell hybridization.

Narahara et al. (1992) described a 7-month-old girl with a terminal
deletion of chromosome 22: del(22)(q13.31). They demonstrated partial
deficiency of arylsulfatase A (ARSA; 607574) and normal levels of
CYB5R3, suggesting that the ARSA locus can be regionally assigned to
22q13.31-qter and the CYB5R3 locus excluded from the same segment.

MOLECULAR GENETICS

Electrophoretic variants of red cell NADH-diaphorase were described by
Hopkinson et al. (1970). Data on gene frequencies of allelic variants
were tabulated by Roychoudhury and Nei (1988).

In sibs with type II methemoglobinemia (250800), characterized by
neurologic involvement, Kobayashi et al. (1990) identified a homozygous
mutation in the CYB5R3 gene (S128P; 613213.0001). Enzyme activity in
patient lymphoblastoid cells was reduced to 10% of normal.

In a patient with type I hereditary methemoglobinemia (250800),
characterized only by cyanosis and no neurologic involvement, Katsube et
al. (1991) found a homozygous mutation in the CYB5R3 gene (R58Q;
613213.0002). In an Italian patient with type I methemoglobinemia,
Shirabe et al. (1992) identified a homozygous mutation in the CYB5R3
gene (V106M; 613213.0004). The mutant enzyme was less heat stable than
the wildtype enzyme.

In 3 unrelated patients with severe recessive congenital
methemoglobinemia type II manifested by cyanosis in association with
severe mental retardation and neurologic impairment, Vieira et al.
(1995) identified homozygous or compound heterozygous mutations in the
CYB5R3 gene (613213.0006-613213.0009).

Percy et al. (2002) stated that 33 different mutations in the CYB5R3
gene causing autosomal recessive congenital methemoglobinemia had been
reported.

Maran et al. (2005) reported 4 unrelated patients with recessive
methemoglobinemia: 2 with type I and 2 with type II. Four different
mutations in the CYB5R3 gene were identified (see, e.g., 613213.0008 and
613218.0012). Methemoglobin levels ranged from 12 to 30%.

GENOTYPE/PHENOTYPE CORRELATIONS

Shirabe (1997) pointed out that missense mutations found in patients
with type II methemoglobinemia are located close to the catalytic center
of the enzyme and the recombinant mutant enzymes have low catalytic
efficiency, whereas mutations in patients with type I are in the
marginal portion of the enzyme, which may only be detrimental to the
stability of the enzyme.

Aalfs et al. (2000) presented a diagram of the CYB5R3 gene showing the
location of 6 mutations that cause methemoglobinemia type I and 13
mutations that cause type II. It appeared that type II was more often
associated with full stops or deletions, whereas type I was more likely
to be associated with amino acid substitutions.

Dekker et al. (2001) investigated 7 families with methemoglobinemia type
I and found 7 novel mutations in the b5R gene. Six of these mutations
predicted amino acid substitutions at sites not involved in reduced NADH
or FAD binding. The seventh mutation, a splice site mutation leading to
skipping of exon 5 in mRNA, was present in heterozygous form together
with a missense mutation on the other allele. Two other substitutions
known to cause the type II form of the disease were found to affect the
consensus FAD-binding site directly or influence NADH binding
indirectly. These data supported the idea that enzyme inactivation is a
cause of type II disease, whereas enzyme instability may lead to the
type I form.

*FIELD* AV
.0001
METHEMOGLOBINEMIA, TYPE II
CYB5R3, SER128PRO

This variant, originally reported as SER127PRO, has been designated
SER128PRO based on revised numbering (Percy and Lappin, 2008).

In sibs with type II methemoglobinemia (250800), Kobayashi et al. (1990)
identified a homozygous 382T-C transition in exon 5 of the CYB5R3 gene,
resulting in a ser128-to-pro (S128P) substitution. Enzyme activity in
patient lymphoblastoid cells was reduced to 10% of normal controls, but
mRNA and protein were detectable. The mutation was predicted to be in an
alpha-helix structure that is part of a nucleotide-binding domain,
suggesting that it caused a significant conformation change and
functional enzyme deficiency.

Yubisui et al. (1991) prepared and characterized mutant enzymes in which
ser128 was replaced by pro (S128P) or by ala (S128A) by utilizing the
expression system of the soluble form of the enzyme in Escherichia coli
and by site-directed mutagenesis. The purified mutant enzymes showed
indistinguishable spectral properties, which differed from those of the
wildtype enzyme, and were less thermostable than the wildtype enzymes.
The results indicated that ser128 plays an important role in maintaining
the structure of the NADH-binding site in the enzyme. The numbering of
ser128 is for the membrane-bound form of b5R, which has 300 residues.
This variant was referred to as 'b5R Hiroshima.'

.0002
METHEMOGLOBINEMIA, TYPE I
CYB5R3, ARG58GLN

This variant, originally reported as ARG57GLN, has been designated
ARG58GLN based on revised numbering (Percy and Lappin, 2008).

In a patient with type I hereditary methemoglobinemia (250800), Katsube
et al. (1991) found a 173G-A transition in exon 3 of the CYB5R3 gene,
resulting in an arg58-to-gln (R58Q) substitution. The mutation abolished
the MspI recognition site. Homozygosity for the mutation was confirmed
by restriction analysis of PCR-amplified fragments and by dot-blot
hybridization of amplified products with allele-specific oligonucleotide
probes. This variant was referred to as 'b5R Toyoake.'

.0003
METHEMOGLOBINEMIA, TYPE I
CYB5R3, LEU149PRO

This variant, originally reported as LEU148PRO, has been designated
LEU149PRO based on revised numbering (Percy and Lappin, 2008).

In 2 Japanese brothers, born of consanguineous parents, with hereditary
methemoglobinemia (250800) without neurologic impairment (Tanishima et
al., 1985), Katsube et al. (1991) found a homozygous 446T-C transition
in exon 5 of the CYB5R3 gene, resulting in a leu148-to-pro (L148P)
substitution. The mutation generated a recognition site for MspI. This
variant was referred to as 'b5R Kurobe.' Deficiency of NADH cytochrome
b5 reductase was observed in lymphocytes and platelets as well as in
erythrocytes, but there was no associated mental retardation. Katsube et
al. (1991) referred to this as 'type III.'

By in vitro functional studies, Nagai et al. (1993) found that the
mutant L159P enzyme retained about 60% of the catalytic activity of
wildtype, but was remarkably heat unstable. Incubation of the mutant
enzyme at 42 degrees C for 10 minutes resulted in 80% loss of enzyme
activity, whereas the wildtype enzyme lost less than 20% activity after
incubation at 50 degrees C for 30 minutes. Another mutant in which
leu149 was replaced by ala also showed decreased heat stability compared
to wildtype, implying a structural role for leu149. Reinvestigation of
the enzyme activity in the blood cells and fibroblasts of the type III
Kurobe patient (Katsube et al., 1991) revealed that about 40% of the
normal activity was detectable in these cells, in contrast to the
previous report. Thus, these patients, previously reported as having
hereditary methemoglobinemia type III, were shown to have type I. This
indicated that the designation of a type III methemoglobinemia is not
necessary because the sole family with this type actually had type I
disease.

.0004
METHEMOGLOBINEMIA, TYPE I
CYB5R3, VAL106MET

This variant, originally reported as VAL105MET, has been designated
VAL106MET based on revised numbering (Percy and Lappin, 2008).

In an Italian patient with type I methemoglobinemia (250800), Shirabe et
al. (1992) identified a 316G-A transition in exon 4 of the CYB5R3 gene,
resulting in a val106-to-met (V106M) substitution. The mutant enzyme was
less heat stable than the wildtype enzyme.

.0005
METHEMOGLOBINEMIA, TYPE II
CYB5R3, IVS8AS, G-T, -1

In the cultured fibroblasts of a patient with generalized deficiency of
NADH-cytochrome b5 reductase (type II methemoglobinemia; 250800),
Shirabe et al. (1995) identified a homozygous G-to-T transversion in
intron 8 of the CYB5R3 gene, resulting in a splice site mutation and
complete absence of immunologically detectable enzyme in blood cells and
skin fibroblasts. The patient was the daughter of Italian second-cousin
parents. She had appeared cyanotic from the first days of life, and
showed failure to thrive and psychomotor developmental delay. At 1 year
of age, she had severe spastic and dystonic quadriparesis with
hyperkinetic involuntary movements, severe microcephaly, and very simple
and primitive reactions to environmental changes. She also developed
refractory seizures. At the age of 9 years, the patient was in a
vegetative status. Cultured fibroblasts of the patient showed severely
reduced NADH-dependent cytochrome c reductase, ferricyanide reductase,
and semidehydroascorbate reductase activities. The last activity is
known to be due to enzyme located on outer mitochondrial membranes;
thus, their results demonstrated that the reductase in the endoplasmic
reticulum and in the outer mitochondrial membranes are the product of
the same gene and suggested that a defect in ascorbate regeneration may
contribute to the phenotype of hereditary methemoglobinemia of the
generalized type.

.0006
METHEMOGLOBINEMIA, TYPE II
CYB5R3, IVS5DS, G-C, +8

In an Algerian patient born of consanguineous parents with type II
methemoglobinemia, Vieira et al. (1995) identified a deletion of exon 5
of the CYB5R3 gene resulting from a G-to-C transversion in intron 5 at
position +8, downstream from the 5-prime splice site of exon 5. Abnormal
splicing of the primary transcripts apparently resulted in a frameshift
with a premature stop codon. The patient was homozygous for the
mutation.

.0007
METHEMOGLOBINEMIA, TYPE II
CYB5R3, ARG219TER

This variant, originally reported as ARG218TER, has been designated
ARG219TER based on revised numbering (Percy and Lappin, 2008).

In an Algerian patient with clinical manifestations of congenital
methemoglobinemia type II (250800), Vieira et al. (1995) identified
homozygosity for an arg219-to-ter (R219X) substitution in exon 8 of the
CYB5R3 gene. The patient had profound mental retardation, microcephaly,
and bilateral athetosis associated with cyanosis and absent enzyme
activities in erythrocytes, lymphocytes, and lymphoblastoid cell lines,

.0008
METHEMOGLOBINEMIA, TYPE II
CYB5R3, CYS204ARG

This variant, originally reported as CYS203ARG, has been designated
CYS204ARG based on revised numbering (Percy and Lappin, 2008).

In a child with methemoglobinemia type II (250800), Vieira et al. (1995)
identified compound heterozygosity for 2 mutations in the CYB5R3 gene: a
T-to-C transition in exon 7 resulting in a cys204-to-arg (C204R)
substitution, and 3-bp deletion (met273del; 613213.0009). The diagnosis
was established at the age of 15 days on the basis of persistent
cyanosis and neurologic manifestations associated with complete enzyme
deficiency in erythrocytes and lymphocytes. Heterozygous levels of
enzyme were detected in both parents who were not related; the mother
was of Spanish ancestry and the father French. One allele carried a
missense mutation with replacement of cys203

Maran et al. (2005) reported a patient with type II methemoglobinemia
resulting from the C204R mutation. There was 30% methemoglobin; CYB5R3
activity was 50% in red blood cells and 25% in cultured lymphocytes.

.0009
METHEMOGLOBINEMIA, TYPE II
CYB5R3, 3-BP DEL, MET273DEL

This variant, originally reported as MET272DEL, has been designated
MET273DEL based on revised numbering (Percy and Lappin, 2008).

See 613213.0008 and Vieira et al. (1995).

.0010
METHEMOGLOBINEMIA, TYPE II
CYB5R3, 3-BP DEL, 895TTC

This variant, originally reported as PHE298DEL, has been designated
PHE299DEL based on revised numbering (Percy and Lappin, 2008).

In a Japanese patient from Yokohoma with type II methemoglobinemia
(250800), Shirabe et al. (1994) identified a homozygous 3-bp in-frame
deletion (895delTTC) in exon 9 of the CYB5R3 gene, resulting in a
deletion of phenylalanine at position 299. Although the mechanism
leading to the deletion was still controversial, the slipped mispairing
model was proposed as the most plausible one. The patient, of Japanese
origin from Yokohama, had retarded growth, mental retardation, and
cyanosis. The mutant enzyme activity was 0.4% that of wildtype and much
less thermostable.

.0011
NADH-CYTOCHROME b5 REDUCTASE POLYMORPHISM
CYB5R3, THR117SER

This variant, originally reported as THR116SER, has been designated
THR117SER based on revised numbering (Percy and Lappin, 2008).

Jenkins and Prchal (1997) claimed to have demonstrated the first
polymorphism in the CYB5R3 gene: a C-to-G transversion in exon 5,
resulting in a thr117-to-ser (T117S) substitution. The polymorphism was
found only in African Americans among whom 26 of 112 chromosomes showed
the G form, giving an allele frequency of 0.23. It was not found in 108
Caucasian, 46 Asian, 44 Indo-Aryan, or 14 Arabic chromosomes.
Preliminary studies indicated that the polymorphism did not correlate
with enzyme activity or produce any disease phenotype. It remained to be
determined whether this African-specific polymorphism that apparently
originated recently in human evolution provides any special survival
advantage.

.0012
METHEMOGLOBINEMIA, TYPE II
CYB5R3, IVS5AS, A-C, -2

In a 4-year-old boy with type II methemoglobinemia (250800), Owen et al.
(1997) identified a homozygous in-frame deletion of exon 6 that resulted
in the deletion of 28 amino acids (codons 155 to 182). A homozygous
A-to-C transversion of the invariant AG dinucleotide of the intron 5
splice acceptor site was discovered and considered to be consistent with
skipping of exon 6. The patient had dystonic athetoid cerebral palsy
with mental retardation and microcephaly. He was found to have 60%
methemoglobin that was persistent but responded to ascorbic acid
treatment.

Maran et al. (2005) reported a patient with type II methemoglobinemia
resulting from the IVS5AS splice site mutation. The patient had 20%
methemoglobin. Four different mRNA transcripts were identified: a normal
transcript, an in-frame skipping of exon 6, and 2 transcripts with
partial inclusion of intron 6. Overall, mRNA levels were 7% of normal
controls. CYB5R3 activity was 2% of controls in red blood cells and 25%
in cultured lymphocytes.

.0013
METHEMOGLOBINEMIA, TYPE I
CYB5R3, LEU73PRO

This variant, originally reported as LEU72PRO, has been designated
LEU73PRO based on revised numbering (Percy and Lappin, 2008).

In a 3-year-old Chinese girl with type I methemoglobinemia (230800), Wu
et al. (1998) identified a homozygous T-to-C transition in the CYB5R3
gene, resulting in a leu73-to-pro (L73P) substitution. The patient was
born after normal pregnancy and delivery. From the age of 1 month she
appeared persistently cyanosed, but without mental or neurologic
abnormalities, and her respiratory and cardiac functions were normal.
The concentration of methemoglobin was 15%, and NADH-cytochrome b5R
activity in erythrocytes was decreased. Her 5-year-old brother had the
same symptoms with 14.5% methemoglobin and decreased b5R activity. The
unaffected parents had heterozygous levels of enzyme activity in red
cells (about 65% of normal controls).

.0014
METHEMOGLOBINEMIA, TYPE II
CYB5R3, GLN77TER

In a patient with methemoglobinemia type II (250800), Aalfs et al.
(2000) identified compound heterozygosity for 2 nonsense mutations in
the CYB5R3 gene: a gln77-to-ter (Q77X) mutation in exon 4 and an
arg160-to-ter mutation (R160X; 613213.0015) in exon 6. The affected
child, born of healthy, unrelated Hindustani Suriname parents, was small
for gestational age. Central cyanosis was noted shortly after birth. She
showed severe psychomotor retardation and microcephaly. There were
athetoid movements, generalized hypertonia, epilepsy, and a complete
head lag. At 6 years of age, MRI of the brain demonstrated frontal and
bitemporal cortical atrophy, cerebellar atrophy, retarded myelin
development, and hypoplasia of the basal ganglia. There was almost no
psychomotor development and spastic tetraplegia with scoliosis was
becoming evident. The patient died at the age of 8 years.

.0015
METHEMOGLOBINEMIA, TYPE II
CYB5R3, ARG160TER

See (613213.0014) and Aalfs et al. (2000).

.0016
METHEMOGLOBINEMIA, TYPE I
CYB5R3, CYS204TYR

This variant, originally reported as CYS203TYR, has been designated
CYS204TYR based on revised numbering (Percy and Lappin, 2008).

In a Chinese family, Wang et al. (2000) found that type I recessive
congenital methemoglobinemia (250800) was caused by homozygosity for a
G-to-A transition in exon 7 of the CYB5R3 gene, resulting in a
cys204-to-tyr (C204Y) substitution. A previously identified mutation in
the same codon, C204R (613213.0008), led to type II methemoglobinemia.
The milder manifestations in the patients studied by Wang et al. (2000)
was thought to be due to the fact that the catalytic activity of the
enzyme was not much affected, although the mutant enzyme exhibited
decreased heat stability and increased susceptibility to trypsin.

.0017
METHEMOGLOBINEMIA, TYPE I
CYB5R3, GLY292ASP

This variant, originally reported as GLY291ASP, has been designated
GLY292ASP based on revised numbering (Percy and Lappin, 2008).

In 1 of the original patients with type I recessive congenital
methemoglobulinemia (250800) from the studies of Deeny et al. (1943) and
Gibson (1948), Percy et al. (2002) identified heterozygosity for 2 novel
mutations in exon 9 of the CYB5R3 gene: a G-to-A transition predicting a
gly292-to-asp (G292D) substitution, and a 3-bp in-frame deletion of
codon 255 (GAG) (613213.0018), predicting loss of glutamic acid. Both
mutations occurred in the carboxyl-terminal NADH-binding lobe of the
protein. Using functional expression studies, Percy et al. (2005) showed
that the mutant G292D enzyme retained approximately 58% of residual
enzyme activity.

.0018
METHEMOGLOBINEMIA, TYPE I
CYB5R3, GLU256DEL

This variant, originally reported as GLU255DEL, has been designated
GLU256DEL based on revised numbering (Percy and Lappin, 2008).

See Percy et al. (2002) and 613213.0017. Using functional expression
studies, Percy et al. (2005) showed that the E256 deletion enzyme
retained approximately 38% of residual enzyme activity.

.0019
METHEMOGLOBINEMIA, TYPE I
CYB5R3, ASP240GLY

This variant, originally reported as ASP239GLY, has been designated
ASP240GLY based on revised numbering (Percy and Lappin, 2008).

In an Irish patient with type I methemoglobulinemia (250800), Percy et
al. (2005) identified a homozygous A-to-G transition in exon 8 of the
CYB5R3 gene, resulting in an asp240-to-gly (D240G) substitution within
the carboxyl-terminal NADH-binding lobe of the protein. In an unrelated
Irish family, 2 sibs with type I methemoglobulinemia were compound
heterozygous for the D240G mutation and another CYB5R3 mutation.
Functional expression studies showed that the D240G mutation retained
substantial enzyme activity, but had perturbed substrate binding,
causing both decreased specificity for NADH and increased specificity
for NADPH.

*FIELD* SA
Board and Pidcock (1981); Choury et al. (1981); Francke et al. (1981);
Gonzalez et al. (1978); Hors-Cayla et al. (1981); Junien et al. (1978);
Kaplan and Beutler (1967); Lostanlen et al. (1981); Tanishima et al.
(1980); Yubisui et al. (1986)
*FIELD* RF
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*FIELD* CN
Ada Hamosh - updated: 12/14/2012

*FIELD* CD
Cassandra L. Kniffin: 1/11/2010

*FIELD* ED
alopez: 12/19/2012
terry: 12/14/2012
terry: 11/5/2010
terry: 11/3/2010
carol: 1/20/2010
ckniffin: 1/13/2010

RBCC Red Blood Cell Collection

Full text data of CYB5R3