RBCC Red Blood Cell Collection

CYBA [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Cytochrome b-245 light chain (Cytochrome b(558) alpha chain; Cytochrome b558 subunit alpha; Neutrophil cytochrome b 22 kDa polypeptide; Superoxide-generating NADPH oxidase light chain subunit; p22 phagocyte B-cytochrome; p22-phox; p22phox)

UniProt P13498
ID CY24A_HUMAN Reviewed; 195 AA.
AC P13498; Q14090; Q9BR72;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 02-NOV-2010, sequence version 3.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Cytochrome b-245 light chain;
DE AltName: Full=Cytochrome b(558) alpha chain;
DE AltName: Full=Cytochrome b558 subunit alpha;
DE AltName: Full=Neutrophil cytochrome b 22 kDa polypeptide;
DE AltName: Full=Superoxide-generating NADPH oxidase light chain subunit;
DE AltName: Full=p22 phagocyte B-cytochrome;
DE AltName: Full=p22-phox;
DE Short=p22phox;
GN Name=CYBA;
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], PROTEIN SEQUENCE OF 2-26, AND VARIANTS
RP HIS-72 AND ALA-174.
RX PubMed=3368442; DOI=10.1073/pnas.85.10.3319;
RA Parkos C.A., Dinauer M.C., Walker L.E., Allen R.A., Jesaitis A.J.,
RA Orkin S.H.;
RT "Primary structure and unique expression of the 22-kilodalton light
RT chain of human neutrophil cytochrome b.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:3319-3323(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-174.
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 (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-174.
RC TISSUE=Brain;
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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 12-123, AND VARIANT ARCGD
RP ARG-118.
RX PubMed=2243141; DOI=10.1172/JCI114898;
RA Dinauer M.C., Pierce E.A., Bruns G.A.P., Curnutte J.T., Orkin S.H.;
RT "Human neutrophil cytochrome b light chain (p22-phox). Gene structure,
RT chromosomal location, and mutations in cytochrome-negative autosomal
RT recessive chronic granulomatous disease.";
RL J. Clin. Invest. 86:1729-1737(1990).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 51-195, AND VARIANTS HIS-72 AND ALA-174.
RX PubMed=2469497;
RA Verhoeven A.J., Bolscher B.G., Meerhof L.J., van Zwieten R.,
RA Keijer J., Weening R.S., Roos D.;
RT "Characterization of two monoclonal antibodies against cytochrome b558
RT of human neutrophils.";
RL Blood 73:1686-1694(1989).
RN [7]
RP INTERACTION WITH NOXO1, AND MUTAGENESIS OF PRO-157.
RX PubMed=12716910; DOI=10.1074/jbc.M212856200;
RA Takeya R., Ueno N., Kami K., Taura M., Kohjima M., Izaki T., Nunoi H.,
RA Sumimoto H.;
RT "Novel human homologues of p47phox and p67phox participate in
RT activation of superoxide-producing NADPH oxidases.";
RL J. Biol. Chem. 278:25234-25246(2003).
RN [8]
RP SUBCELLULAR LOCATION, AND MEMBRANE TOPOLOGY.
RX PubMed=15585859;
RA Taylor R.M., Burritt J.B., Baniulis D., Foubert T.R., Lord C.I.,
RA Dinauer M.C., Parkos C.A., Jesaitis A.J.;
RT "Site-specific inhibitors of NADPH oxidase activity and structural
RT probes of flavocytochrome b: characterization of six monoclonal
RT antibodies to the p22phox subunit.";
RL J. Immunol. 173:7349-7357(2004).
RN [9]
RP INTERACTION WITH DUOX1; DUOX2 AND TPO.
RX PubMed=15561711; DOI=10.1074/jbc.M407709200;
RA Wang D., De Deken X., Milenkovic M., Song Y., Pirson I., Dumont J.E.,
RA Miot F.;
RT "Identification of a novel partner of duox: EFP1, a thioredoxin-
RT related protein.";
RL J. Biol. Chem. 280:3096-3103(2005).
RN [10]
RP FUNCTION.
RX PubMed=15824103; DOI=10.1074/jbc.M414548200;
RA Ueno N., Takeya R., Miyano K., Kikuchi H., Sumimoto H.;
RT "The NADPH oxidase Nox3 constitutively produces superoxide in a
RT p22phox-dependent manner: its regulation by oxidase organizers and
RT activators.";
RL J. Biol. Chem. 280:23328-23339(2005).
RN [11]
RP INTERACTION WITH NOX4.
RX PubMed=15927447; DOI=10.1016/j.cellsig.2005.03.023;
RA Martyn K.D., Frederick L.M., von Loehneysen K., Dinauer M.C.,
RA Knaus U.G.;
RT "Functional analysis of Nox4 reveals unique characteristics compared
RT to other NADPH oxidases.";
RL Cell. Signal. 18:69-82(2006).
RN [12]
RP PHOSPHORYLATION AT THR-147.
RX PubMed=19948736; DOI=10.1074/jbc.M109.030643;
RA Lewis E.M., Sergeant S., Ledford B., Stull N., Dinauer M.C.,
RA McPhail L.C.;
RT "Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase
RT activity by promoting p47phox binding.";
RL J. Biol. Chem. 285:2959-2967(2010).
RN [13]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH CALPROTECTIN.
RX PubMed=22808130; DOI=10.1371/journal.pone.0040277;
RA Berthier S., Nguyen M.V., Baillet A., Hograindleur M.A., Paclet M.H.,
RA Polack B., Morel F.;
RT "Molecular interface of S100A8 with cytochrome b and NADPH oxidase
RT activation.";
RL PLoS ONE 7:E40277-E40277(2012).
RN [14]
RP STRUCTURE BY NMR OF 149-167 IN COMPLEX WITH NCF1, AND INTERACTION WITH
RP NCF1.
RX PubMed=16326715; DOI=10.1074/jbc.M505193200;
RA Ogura K., Nobuhisa I., Yuzawa S., Takeya R., Torikai S., Saikawa K.,
RA Sumimoto H., Inagaki F.;
RT "NMR solution structure of the tandem Src homology 3 domains of
RT p47phox complexed with a p22phox-derived proline-rich peptide.";
RL J. Biol. Chem. 281:3660-3668(2006).
RN [15]
RP VARIANTS ARCGD GLN-90 AND ARG-94.
RX PubMed=1415254;
RA de Boer M., de Klein A., Hossle J.-P., Seger R., Corbeel L.,
RA Weening R.S., Roos D.;
RT "Cytochrome b558-negative, autosomal recessive chronic granulomatous
RT disease: two new mutations in the cytochrome b558 light chain of the
RT NADPH oxidase (p22-phox).";
RL Am. J. Hum. Genet. 51:1127-1135(1992).
RN [16]
RP VARIANT ARCGD GLN-156.
RX PubMed=1763037; DOI=10.1073/pnas.88.24.11231;
RA Dinauer M.C., Pierce E.A., Erickson R.W., Muhlebach T.J., Messner H.,
RA Orkin S.H., Seger R.A., Curnutte J.T.;
RT "Point mutation in the cytoplasmic domain of the neutrophil p22-phox
RT cytochrome b subunit is associated with a nonfunctional NADPH oxidase
RT and chronic granulomatous disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:11231-11235(1991).
RN [17]
RP VARIANT ARCGD VAL-53.
RX PubMed=8168815; DOI=10.1007/BF00201671;
RA Hossle J.-P., de Boer M., Seger R.A., Roos D.;
RT "Identification of allele-specific p22-phox mutations in a compound
RT heterozygous patient with chronic granulomatous disease by mismatch
RT PCR and restriction enzyme analysis.";
RL Hum. Genet. 93:437-442(1994).
RN [18]
RP CHARACTERIZATION OF VARIANT ARCGD GLN-156.
RX PubMed=7964505; DOI=10.1084/jem.180.6.2329;
RA Leusen J.H., Bolscher B.G., Hilarius P.M., Weening R.S.,
RA Kaulfersch W., Seger R.A., Roos D., Verhoeven A.J.;
RT "156Pro-->Gln substitution in the light chain of cytochrome b558 of
RT the human NADPH oxidase (p22-phox) leads to defective translocation of
RT the cytosolic proteins p47-phox and p67-phox.";
RL J. Exp. Med. 180:2329-2334(1994).
RN [19]
RP VARIANTS ARCGD ARG-24; VAL-25; PRO-52; TRP-90 AND ARG-118.
RX PubMed=10910929;
RA Rae J., Noack D., Heyworth P.G., Ellis B.A., Curnutte J.T.,
RA Cross A.R.;
RT "Molecular analysis of 9 new families with chronic granulomatous
RT disease caused by mutations in CYBA, the gene encoding p22(phox).";
RL Blood 96:1106-1112(2000).
RN [20]
RP VARIANT ARCGD ARG-24.
RX PubMed=10759707; DOI=10.1046/j.1365-2141.2000.01857.x;
RA Yamada M., Ariga T., Kawamura N., Ohtsu M., Imajoh-Ohmi S.,
RA Ohshika E., Tatsuzawa O., Kobayashi K., Sakiyama Y.;
RT "Genetic studies of three Japanese patients with p22-phox-deficient
RT chronic granulomatous disease: detection of a possible common mutant
RT CYBA allele in Japan and a genotype-phenotype correlation in these
RT patients.";
RL Br. J. Haematol. 108:511-517(2000).
RN [21]
RP VARIANTS ARCGD ARG-24 AND VAL-124.
RX PubMed=10914676; DOI=10.1007/s004390000288;
RA Ishibashi F., Nunoi H., Endo F., Matsuda I., Kanegasaki S.;
RT "Statistical and mutational analysis of chronic granulomatous disease
RT in Japan with special reference to gp91-phox and p22-phox
RT deficiency.";
RL Hum. Genet. 106:473-481(2000).
RN [22]
RP VARIANT ARCGD THR-125.
RX PubMed=18422995; DOI=10.1111/j.1365-2141.2008.07148.x;
RA Teimourian S., Zomorodian E., Badalzadeh M., Pouya A.,
RA Kannengiesser C., Mansouri D., Cheraghi T., Parvaneh N.;
RT "Characterization of six novel mutations in CYBA: the gene causing
RT autosomal recessive chronic granulomatous disease.";
RL Br. J. Haematol. 141:848-851(2008).
RN [23]
RP VARIANTS HIS-72; GLY-171; ALA-174 AND ASP-193.
RX PubMed=19388116; DOI=10.1002/humu.21029;
RA Bedard K., Attar H., Bonnefont J., Jaquet V., Borel C., Plastre O.,
RA Stasia M.-J., Antonarakis S.E., Krause K.-H.;
RT "Three common polymorphisms in the CYBA gene form a haplotype
RT associated with decreased ROS generation.";
RL Hum. Mutat. 30:1123-1133(2009).
CC -!- FUNCTION: Critical component of the membrane-bound oxidase of
CC phagocytes that generates superoxide. Associates with NOX3 to form
CC a functional NADPH oxidase constitutively generating superoxide.
CC -!- SUBUNIT: Composed of a heavy chain (beta) and a light chain
CC (alpha). Component of an NADPH oxidase complex composed of a
CC heterodimer formed by the membrane proteins CYBA and CYBB and the
CC cytosolic subunits NCF1, NCF2 and NCF4. Interacts with NCF1 (via
CC SH3 domain). Interacts with SH3PXD2A (By similarity). Interacts
CC with DUOX1, DUOX2 and TPO. Interacts with NOX3 and NOX4. Interacts
CC with calprotectin (S100A8/9).
CC -!- INTERACTION:
CC P14598:NCF1; NbExp=7; IntAct=EBI-986058, EBI-395044;
CC Q8NFA2:NOXO1; NbExp=6; IntAct=EBI-986058, EBI-7130806;
CC -!- SUBCELLULAR LOCATION: Cell membrane.
CC -!- PTM: The heme prosthetic group could be coordinated with residues
CC of the light chain, the heavy chain, or both, and it is possible
CC that more than one heme is present per cytochrome b-245.
CC -!- PTM: Phosphorylation at Thr-147 enhances NADPH oxidase activity by
CC promoting p47phox binding (By similarity).
CC -!- DISEASE: Granulomatous disease, chronic, cytochrome-b-negative,
CC autosomal recessive (ARCGD) [MIM:233690]: A disorder characterized
CC by the inability of neutrophils and phagocytes to kill microbes
CC that they have ingested. Patients suffer from life-threatening
CC bacterial/fungal infections. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the p22phox family.
CC -!- WEB RESOURCE: Name=CYBAbase; Note=CYBA mutation db;
CC URL="http://bioinf.uta.fi/CYBAbase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CYBA";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=C&genename;=CYBB+%40+GP91-PHOX";
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DR EMBL; M21186; AAA90925.1; -; mRNA.
DR EMBL; BT006861; AAP35507.1; -; mRNA.
DR EMBL; AC116552; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC006465; AAH06465.1; -; mRNA.
DR EMBL; AH002664; AAA52134.1; -; Genomic_DNA.
DR PIR; A28201; A28201.
DR RefSeq; NP_000092.2; NM_000101.3.
DR UniGene; Hs.513803; -.
DR PDB; 1WLP; NMR; -; A=149-167.
DR PDBsum; 1WLP; -.
DR ProteinModelPortal; P13498; -.
DR DIP; DIP-37650N; -.
DR IntAct; P13498; 7.
DR MINT; MINT-5209680; -.
DR STRING; 9606.ENSP00000261623; -.
DR TCDB; 5.B.1.1.1; the phagocyte (gp91(phox)) nadph oxidase family.
DR PhosphoSite; P13498; -.
DR DMDM; 311033459; -.
DR PaxDb; P13498; -.
DR PeptideAtlas; P13498; -.
DR PRIDE; P13498; -.
DR DNASU; 1535; -.
DR Ensembl; ENST00000261623; ENSP00000261623; ENSG00000051523.
DR GeneID; 1535; -.
DR KEGG; hsa:1535; -.
DR UCSC; uc002flb.4; human.
DR CTD; 1535; -.
DR GeneCards; GC16M088709; -.
DR H-InvDB; HIX0013335; -.
DR HGNC; HGNC:2577; CYBA.
DR HPA; CAB009492; -.
DR MIM; 233690; phenotype.
DR MIM; 608508; gene.
DR neXtProt; NX_P13498; -.
DR Orphanet; 379; Chronic granulomatous disease.
DR PharmGKB; PA27075; -.
DR eggNOG; NOG39609; -.
DR HOGENOM; HOG000001585; -.
DR HOVERGEN; HBG051278; -.
DR InParanoid; P13498; -.
DR KO; K08009; -.
DR OMA; KIEWAMW; -.
DR PhylomeDB; P13498; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; CYBA; human.
DR EvolutionaryTrace; P13498; -.
DR GenomeRNAi; 1535; -.
DR NextBio; 6349; -.
DR PRO; PR:P13498; -.
DR ArrayExpress; P13498; -.
DR Bgee; P13498; -.
DR CleanEx; HS_CYBA; -.
DR Genevestigator; P13498; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0043020; C:NADPH oxidase complex; IDA:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0030670; C:phagocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0030141; C:secretory granule; TAS:BHF-UCL.
DR GO; GO:0009055; F:electron carrier activity; TAS:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0002479; P:antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; TAS:Reactome.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0071480; P:cellular response to gamma radiation; IEA:Ensembl.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0017004; P:cytochrome complex assembly; IDA:BHF-UCL.
DR GO; GO:0050665; P:hydrogen peroxide biosynthetic process; ISS:BHF-UCL.
DR GO; GO:0006954; P:inflammatory response; IMP:BHF-UCL.
DR GO; GO:0045087; P:innate immune response; IMP:BHF-UCL.
DR GO; GO:0051701; P:interaction with host; TAS:Reactome.
DR GO; GO:0003106; P:negative regulation of glomerular filtration by angiotensin; IEA:Ensembl.
DR GO; GO:0055114; P:oxidation-reduction process; IMP:BHF-UCL.
DR GO; GO:0090382; P:phagosome maturation; TAS:Reactome.
DR GO; GO:0030307; P:positive regulation of cell growth; IEA:Ensembl.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:0045730; P:respiratory burst; IMP:BHF-UCL.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0070555; P:response to interleukin-1; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0014895; P:smooth muscle hypertrophy; ISS:BHF-UCL.
DR GO; GO:0042554; P:superoxide anion generation; IMP:BHF-UCL.
DR InterPro; IPR007732; Cyt_b558_asu.
DR PANTHER; PTHR15168; PTHR15168; 1.
DR Pfam; PF05038; Cytochrom_B558a; 1.
DR PIRSF; PIRSF019635; Cytochr_b558a; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Chronic granulomatous disease;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Electron transport; Heme; Iron; Membrane; Metal-binding; NADP;
KW Oxidoreductase; Phosphoprotein; Polymorphism; Reference proteome;
KW Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 195 Cytochrome b-245 light chain.
FT /FTId=PRO_0000144907.
FT INTRAMEM 91 127
FT COMPBIAS 133 189 Pro-rich.
FT METAL 94 94 Iron (heme axial ligand) (Potential).
FT MOD_RES 168 168 Phosphoserine (By similarity).
FT VARIANT 24 24 G -> R (in ARCGD; dbSNP:rs28941476).
FT /FTId=VAR_012755.
FT VARIANT 25 25 G -> V (in ARCGD; dbSNP:rs179363891).
FT /FTId=VAR_060576.
FT VARIANT 52 52 L -> P (in ARCGD; dbSNP:rs179363890).
FT /FTId=VAR_060577.
FT VARIANT 53 53 E -> V (in ARCGD; dbSNP:rs179363893).
FT /FTId=VAR_060578.
FT VARIANT 72 72 Y -> H (in dbSNP:rs4673).
FT /FTId=VAR_005122.
FT VARIANT 90 90 R -> Q (in ARCGD).
FT /FTId=VAR_005123.
FT VARIANT 90 90 R -> W (in ARCGD; dbSNP:rs179363892).
FT /FTId=VAR_060579.
FT VARIANT 94 94 H -> R (in ARCGD).
FT /FTId=VAR_005124.
FT VARIANT 118 118 S -> R (in ARCGD; dbSNP:rs104894514).
FT /FTId=VAR_005125.
FT VARIANT 124 124 A -> V (in ARCGD; dbSNP:rs179363894).
FT /FTId=VAR_060580.
FT VARIANT 125 125 A -> T (in ARCGD).
FT /FTId=VAR_060581.
FT VARIANT 156 156 P -> Q (in ARCGD).
FT /FTId=VAR_005126.
FT VARIANT 171 171 E -> G (in dbSNP:rs72667005).
FT /FTId=VAR_060582.
FT VARIANT 174 174 V -> A (in dbSNP:rs1049254).
FT /FTId=VAR_054801.
FT VARIANT 193 193 E -> D.
FT /FTId=VAR_060583.
FT MUTAGEN 157 157 P->Q: Loss of interaction with NOXO1.
FT HELIX 161 165
SQ SEQUENCE 195 AA; 21013 MW; 428427AD19398240 CRC64;
MGQIEWAMWA NEQALASGLI LITGGIVATA GRFTQWYFGA YSIVAGVFVC LLEYPRGKRK
KGSTMERWGQ KYMTAVVKLF GPFTRNYYVR AVLHLLLSVP AGFLLATILG TACLAIASGI
YLLAAVRGEQ WTPIEPKPRE RPQIGGTIKQ PPSNPPPRPP AEARKKPSEE EAAVAAGGPP
GGPQVNPIPV TDEVV
//

MIM 233690
*RECORD*
*FIELD* NO
233690
*FIELD* TI
#233690 GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
read more;;CGD, AUTOSOMAL RECESSIVE CYTOCHROME b-NEGATIVE;;
CGD DUE TO DEFICIENCY OF THE ALPHA SUBUNIT OF CYTOCHROME b;;
CYBA DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because autosomal recessive
cytochrome b-negative chronic granulomatous disease (CGD) is caused by
mutation in the gene encoding p22-phox (CYBA; 608508).

For a detailed phenotypic description of chronic granulomatous disease,
see X-linked cytochrome b-negative CGD (306400). See also autosomal
recessive cytochrome b-positive CGD, types I (233700) and II (608515).

DESCRIPTION

Chronic granulomatous disease is a genetically heterogeneous
immunodeficiency disorder resulting from an inability of phagocytes to
kill microbes that they have ingested. This impairment in killing is
caused by any of several defects in the NADPH oxidase enzyme complex
which generates the microbicidal 'respiratory burst.'

CLINICAL FEATURES

Baehner and Nathan (1968) observed a 17-year-old female born of first
cousins who showed a clinical course and leukocyte behavior in vitro
like those in affected males with X-linked CGD. Chromosomes were normal.
The nitroblue tetrazolium (NBT) test of leukocytes was normal in all
relatives.

Yamada et al. (2000) reported a 33-year-old Japanese woman with
cytochrome b-negative CGD who had recurrent pneumonia and osteomyelitis
caused by various bacteria and Aspergillus. At the age of 33 years, she
had renal insufficiency as a result of the nephrotoxic side effects of
antifungal drugs and was being treated with hemodialysis. Her parents
were related.

Stasia et al. (2002) reported a 5-year-old girl who presented with
recurrent bacterial infections and mycosis since the first month of
life. The parents were unrelated but lived in a small isolated village
in which autarky was said to have existed for several generations.

Teimourian et al. (2008) reported 8 patients from 7 unrelated
consanguineous Iranian families with cytochrome b-negative CGD. Patients
had a clinical history of recurrent severe infections, including
pneumonia, lymphadenitis, liver abscesses, and pyodermatitis. Four of
the patients presented before 1 year of age. Genetic analysis identified
homozygous mutation or deletion of the CYBA gene (see, e.g.,
608508.0012) in all patients.

BIOCHEMICAL FEATURES

By somatic cell hybridization, Weening et al. (1985) demonstrated an
autosomal form of CGD in which cytochrome b was diminished. Among the
children of first-cousin parents, 2 sisters and a brother had CGD with
granulocytes that did not respond with a metabolic burst to various
stimuli and did not kill catalase-positive microorganisms. The magnitude
of the cytochrome b signal in the optical spectrum of these leukocytes
was less than 4% of normal; the amount of covalently bound flavin was
normal. Autosomal recessive inheritance was confirmed; the granulocytes
of both parents showed intermediate levels of cytochrome b signal,
low-normal or subnormal oxidative reactions during stimulation, and no
mosaicism in the stimulated NBT slide test. When monocytes from these
patients were fused either with monocytes from a male with X-linked
cytochrome b-negative CGD or with monocytes from a male with autosomal
cytochrome b-positive CGD, the hybrid cells showed NBT reductase
activity after stimulation with PMA. This complementation required
protein synthesis. Weening et al. (1985) concluded that the expression
of cytochrome b in human phagocytes is coded by at least 2 loci, one
autosomal and one X-linked.

Parkos et al. (1989) found that neither cytochrome b subunit, p22-phox
or p91-phox (300481), could be detected in neutrophils from 3 patients
with X-linked cytochrome b-negative CGD or in 4 patients with autosomal
cytochrome b-negative CGD. The authors concluded that the stable
expression of either of the 2 subunits is dependent upon the other.

CLINICAL MANAGEMENT

Liese et al. (2000) evaluated the effect of antibiotic and antifungal
long-term prophylaxis on the prognosis of CGD in 39 patients with
different subtypes, both X-linked and autosomal recessive. Antibiotic
prophylaxis with TMP-SMX significantly decreased the incidence of severe
infections in patients with complete loss of cytochrome b activity but
had no significant effect in patients with the other subtypes. Eight of
the patients with complete absence of cytochrome b activity were also
given itraconazole, and none developed fungal infections over 15.5
patient-years, whereas patients of all subtypes who received only
antibiotics showed an increase in severe fungal infections. The
different subtypes were also analyzed for age at diagnosis, age at first
infection, and long-term survival.

MOLECULAR GENETICS

Clark et al. (1989) concluded that the form of CGD caused by mutation in
the CYBA gene represents about 5% of all CGD cases.

In 3 patients with autosomal recessive cytochrome b-negative CGD,
Dinauer et al. (1990) identified 4 mutations in the CYBA gene
(608508.0001-608508.0004). One of the patients had been described by
Baehner and Nathan (1968).

Yamada et al. (2000) performed mutation analysis on 3 female patients
with cytochrome b-negative CGD and found 2 novel mutations in the CYBA
gene. One patient with the severe phenotype had a homozygous nonsense
mutation in exon 1 (608508.0009); the other 2 patients with mild
phenotypes shared the same homozygous missense mutation in exon 2
(608508.0010). The latter 2 patients, but not the first, were
demonstrated to have detectable p22-phox expression and significant
granulocyte respiratory burst activity, consistent with the milder
phenotype.

In a 5-year-old girl with cytochrome b-negative CGD, Stasia et al.
(2002) identified a mutation in the CYBA gene (608508.0011).

ANIMAL MODEL

Nakano et al. (2008) found that induced-mutant nmf333 mice were
deficient in p22-phox protein due to a tyr121-to-his (Y121H) mutation in
the Cyba gene. Homozygous mutant mice showed chronic granulomatous
disease characterized by absence of superoxide production in phagocytes
and complete absence of NADPH oxidase activity. The mutant mice were
highly susceptible to fatal necrotizing B. cepacia pneumonia. In
addition, mutant mice showed a severe balance disorder associated with
complete absence of otoconia in the utricles and saccules of the inner
ear. Transgenic expression of wildtype Cyba rescued both phenotypes.
Studies on wildtype mice found Cyba expression in the endolymphatic
ducts of the embryonic inner ear, which decreased by postnatal day 12.
Based on these findings, Nakano et al. (2008) proposed that NOX activity
in the endolymph of the embryonic inner ear regulates local ionic
conditions and pH, which may favor the crystallization of calcium
carbonate and thereby promote the formation of otoconia. However, the
authors noted that balance disorders had not been described in humans
with CYBA-associated disease.

*FIELD* SA
de Boer et al. (1992)
*FIELD* RF
1. Baehner, R. L.; Nathan, D. G.: Quantitative nitroblue tetrazolium
test in chronic granulomatous disease. New Eng. J. Med. 278: 971-976,
1968.

2. Clark, R. A.; Malech, H. L.; Gallin, J. I.; Nunoi, H.; Volpp, B.
D.; Pearson, D. W.; Nauseef, W. M.; Curnutte, J. T.: Genetic variants
of chronic granulomatous disease: prevalence of deficiencies of two
cytosolic components of the NADPH oxidase system. New Eng. J. Med. 321:
647-652, 1989.

3. de Boer, M.; de Klein, A.; Hossle, J.-P.; Seger, R.; Corbeel, L.;
Weening, R. S.; Roos, D.: Cytochrome b(558)-negative, autosomal recessive
chronic granulomatous disease: two new mutations in the cytochrome
b(558) light chain of the NADPH oxidase (p22-phox). Am. J. Hum. Genet. 51:
1127-1135, 1992.

4. Dinauer, M. C.; Pierce, E. A.; Bruns, G. A. P.; Curnutte, J. T.;
Orkin, S. H.: Human neutrophil cytochrome b light chain (p22-phox):
gene structure, chromosomal location, and mutations in cytochrome-negative
autosomal recessive chronic granulomatous disease. J. Clin. Invest. 86:
1729-1737, 1990.

5. Liese, J.; Kloos, S.; Jendrossek, V.; Petropoulou, T.; Wintergerst,
U.; Notheis, G.; Gahr, M.; Belohradsky, B. H.: Long-term follow-up
and outcome of 39 patients with chronic granulomatous disease. J.
Pediat. 137: 687-693, 2000.

6. Nakano, Y.; Longo-Guess, C. M.; Bergstrom, D. E.; Nauseef, W. M.;
Jones, S. M.; Banfi, B.: Mutation of the Cyba gene encoding p22(phox)
causes vestibular and immune defects in mice. J. Clin. Invest. 118:
1176-1185, 2008.

7. Parkos, C. A.; Dinauer, M. C.; Jesaitis, A. J.; Orkin, S. H.; Curnutte,
J. T.: Absence of both the 91kD and 22kD subunits of human neutrophil
cytochrome b in two genetic forms of chronic granulomatous disease. Blood 73:
1416-1420, 1989.

8. Stasia, M. J.; Bordigoni, P.; Martel, C.; Morel, F.: A novel and
unusual case of chronic granulomatous disease in a child with a homozygous
36-bp deletion in the CYBA gene (A22-0) leading to the activation
of a cryptic splice site in intron 4. Hum. Genet. 110: 444-450,
2002.

9. Teimourian, S.; Zomorodian, E.; Badalzadeh, M.; Pouya, A.; Kannengiesser,
C.; Mansouri, D.; Cheraghi, T.; Parvaneh, N.: Characterization of
six novel mutations in CYBA: the gene causing autosomal recessive
chronic granulomatous disease. Brit. J. Haemat. 141: 848-851, 2008.

10. Weening, R. S.; Corbeel, L.; de Boer, M.; Lutter, R.; van Zwieten,
R.; Hamers, M. N.; Roos, D.: Cytochrome b deficiency in an autosomal
form of chronic granulomatous disease: a third form of chronic granulomatous
disease recognized by monocyte hybridization. J. Clin. Invest. 75:
915-920, 1985.

11. Yamada, M.; Ariga, T.; Kawamura, N.; Ohtsu, M.; Imajoh-Ohmi, S.;
Ohshika, E.; Tatsuzawa, O.; Kobayashi, K.; Sakiyama, Y.: Genetic
studies of three Japanese patients with p22-phox-deficient chronic
granulomatous disease: detection of a possible common mutant CYBA
allele in Japan and a genotype-phenotype correlation in these patients. Brit.
J. Haemat. 108: 511-517, 2000.

*FIELD* CS
INHERITANCE:
Autosomal recessive

RESPIRATORY:
[Lung];
Pneumonia due to immunodeficiency

ABDOMEN:
[Liver];
Hepatic abscesses due to immunodeficiency;
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Perirectal abscesses due to immunodeficiency

SKELETAL:
Osteomyelitis due to immunodeficiency

SKIN, NAILS, HAIR:
[Skin];
Dermatitis, infectious, due to immunodeficiency Impetigo;
Eczematoid dermatitis;
Discoid lupus in carriers or adults with mild disease

MUSCLE, SOFT TISSUE:
Cellulitis due to immunodeficiency

IMMUNOLOGY:
Bacterial infections, recurrent;
Fungal infections, recurrent;
Absence of bactericidal oxidative 'respiratory burst' in phagocytes;
Abscess formation in any organ;
Lymphadenitis;
Lymphadenopathy;
Aspergillus infections;
Klebsiella infections;
Staphylococcus aureus infections;
E. coli infections;
Burkholderia cepacia infections;
Serratia marcescens infections;
Tissue biopsy shows granulomas;
Biopsy shows lipid-laden macrophages

LABORATORY ABNORMALITIES:
Deficiency or absence of cytochrome b(-245);
Deficiency or absence of p91-phox (300481) protein;
Deficiency or absence of p22-phox protein;
Negative nitroblue tetrazolium (NBT) reduction test;
Decreased activity of NADPH oxidase

MISCELLANEOUS:
Onset usually in first decade;
Four types of CGD with basically identical clinical phenotypes;
X-linked recessive cytochrome b-negative CGD (306400);
Autosomal recessive cytochrome b-positive CGD, type I (233700);
Autosomal recessive cytochrome b-positive CGD, type II (233710)

MOLECULAR BASIS:
Caused by mutation in the cytochrome b(-245) alpha subunit gene (CYBA,
608508.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 3/11/2004

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

*FIELD* ED
joanna: 05/19/2011
joanna: 10/11/2010
joanna: 3/15/2004
ckniffin: 3/15/2004
ckniffin: 3/11/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 5/30/2008
Cassandra L. Kniffin - reorganized: 3/12/2004
Victor A. McKusick - updated: 6/7/2002
Victor A. McKusick - updated: 7/13/2000
Victor A. McKusick - updated: 9/1/1999
Lori M. Kelman - updated: 3/31/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
terry: 06/03/2011
alopez: 2/9/2009
alopez: 2/5/2009
wwang: 1/23/2009
ckniffin: 1/15/2009
wwang: 6/17/2008
ckniffin: 5/30/2008
carol: 3/12/2004
terry: 3/12/2004
ckniffin: 3/12/2004
ckniffin: 3/11/2004
alopez: 6/12/2002
terry: 6/7/2002
carol: 9/11/2001
alopez: 7/21/2000
terry: 7/13/2000
alopez: 11/18/1999
carol: 9/23/1999
jlewis: 9/23/1999
terry: 9/1/1999
alopez: 3/31/1997
mimadm: 2/19/1994
carol: 2/18/1993
carol: 11/12/1992
supermim: 3/16/1992
carol: 1/27/1992
carol: 1/3/1992

MIM 608508
*RECORD*
*FIELD* NO
608508
*FIELD* TI
+608508 CYTOCHROME b(-245), ALPHA SUBUNIT; CYBA
;;CYTOCHROME b(558), ALPHA SUBUNIT;;
read morep22-PHOX;;
CYTOCHROME b LIGHT CHAIN
REACTIVE OXYGEN SPECIES GENERATION, DECREASED, INCLUDED
*FIELD* TX

DESCRIPTION

The CYBA gene encodes the alpha subunit, also known as the light chain,
of cytochrome b(-245), which is a component of the NADPH oxidase (NOX)
complex responsible for the respiratory burst in phagocytes.

The CYBB gene (300481) is an X-linked gene which encodes the cytochrome
b beta subunit, also known as the heavy chain.

Dinauer et al. (1990) and Schapiro et al. (1991) referred to the 22-kD
gene product as p22-phox (for phagocyte oxidase). De Boer et al. (1992)
referred to the product of the CYBA gene as the alpha subunit of
cytochrome b(558) or p22-phox. They mentioned an international agreement
on designations.

CLONING

By screening a cDNA library constructed from human promyelocytic
leukemia cells, Parkos et al. (1988) isolated a cDNA corresponding to
the light chain of cytochrome b. The cDNA encodes a 22-kD protein
comprising 195 amino acids with a high proline content (10%). A database
search showed that a 31-residue region of the protein is 39% identical
to a corresponding region of the heme-bearing subunit (polypeptide I) of
mitochondrial cytochrome c oxidase (516030). Northern blot analysis
detected a 0.8-kb mRNA transcript in all cell lines tested, including
phagocytes, hepatic cells, endothelial cells, B cells, and
erythroleukemic cells, but the 22-kD protein was barely detectable in
the nonphagocytic cells, suggesting a block in translation in these
cells. The stable protein was detected only in phagocytic cells that
were also expressing the larger cytochrome b subunit, p91-phox. Parkos
et al. (1988) concluded that the large subunit may play a role in
regulating the assembly of the heterodimeric cytochrome b.

Fukui et al. (1995) isolated a cDNA for the cytochrome b alpha subunit
(p22-phox) of the NADPH oxidase in rat vascular smooth muscle cells
(VSMCs) and showed that the rat gene is homologous to both the human and
mouse genes.

GENE STRUCTURE

Dinauer et al. (1990) determined that the CYBA gene contains 6 exons and
spans 8.5 kb.

MAPPING

Using Southern blot analysis of DNA from human-rodent somatic cell
hybrids, Bu-Ghanim et al. (1990) demonstrated that the alpha subunit is
encoded by a single locus (CYBA) on chromosome 16. By a combination of
Southern blot analysis of somatic cell hybrids and in situ
hybridization, Dinauer et al. (1990) mapped the CYBA gene to 16q24.

By genomic sequence analysis, Powell et al. (2002) mapped the CYBA gene
to chromosome 16q24.3.

GENE FUNCTION

Ushio-Fukai et al. (1996) provided evidence that p22-phox is a critical
component of the superoxide-generating vascular NADH/NADPH oxidase. They
stably transfected antisense p22-phox cDNA into rat VSMCs and showed
that this results in decreased cytochrome-b content and superoxide
production.

Superoxide anion (O2-) formation occurs in phagocytic cells, such as
neutrophils, macrophages, and monocytes, and is important for the
microbicidal activity of these cells. The production of superoxide anion
is not limited to these cell types, however, and has been implicated in
the pathogenesis of both hypertension and atherosclerosis (Alexander,
1995).

Yazdanpanah et al. (2009) identified riboflavin kinase (RFK, formerly
known as flavokinase; 613010) as a TNFR1 (191190)-binding protein that
physically and functionally couples TNFR1 to NADPH oxidase (300225). In
mouse and human cells, RFK binds to both the TNFR1 death domain and to
p22(phox), the common subunit of NADPH oxidase isoforms. RFK-mediated
bridging of TNFR1 and p22(phox) is a prerequisite for TNF-induced but
not for Toll-like receptor (see 601194)-induced reactive oxygen species
(ROS) production. Exogenous flavin mononucleotide or FAD was able to
substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient
cells. RFK is rate-limiting in the synthesis of FAD, an essential
prosthetic group of NADPH oxidase. Yazdanpanah et al. (2009) concluded
that TNF, through the activation of RFK, enhances the incorporation of
FAD in NADPH oxidase enzymes, a critical step for the assembly and
activation of NADPH oxidase.

MOLECULAR GENETICS

- Autosomal Recessive Cytochrome b-Negative Chronic Granulomatous
Disease

In 3 patients with autosomal recessive cytochrome b-negative CGD
(233690), Dinauer et al. (1990) identified 4 mutations in the CYBA gene
(608508.0001-608508.0004).

Yamada et al. (2000) performed mutation analysis on 3 female patients
with cytochrome b-negative CGD and found 2 novel mutations in the CYBA
gene. One patient with a severe phenotype had a homozygous nonsense
mutation in exon 1 (608508.0009); the other 2 patients with mild
phenotypes shared the same homozygous missense mutation in exon 2
(608508.0010). The latter 2 patients, but not the first, were
demonstrated to have detectable p22-phox expression and significant
granulocyte respiratory burst activity, consistent with the milder
phenotype.

Teimourian et al. (2008) identified homozygous mutations or deletions in
the CYBA gene (see, e.g., 608508.0012) in 8 patients from 7 unrelated
consanguineous Iranian families with cytochrome b-negative CGD. Patients
had a clinical history of recurrent severe infections, including
pneumonia, lymphadenitis, liver abscesses, and pyodermatitis. Four of
the patients presented before 1 year of age.

- Cardiovascular Disease

Parkos et al. (1988) described a 242C-T polymorphism of the CYBA gene
causing a his72-to-tyr change (dbSNP rs4673; 608508.0008). Bedard et al.
(2009) noted that the 242C-T SNP is also referred to as 214T-C (Y72H)
based on numbering from the ATG codon.

Inoue et al. (1998) reported that the presence of the 242T polymorphism
was associated with reduced risk of coronary artery disease (CAD) in
Japanese. This was significant since patients with CAD have impaired
endothelial function in part due to an increase in vascular oxidant
stress.

Li et al. (1999) studied the frequency of the 242T polymorphism in 252
U.S. patients (83% Caucasian) who underwent angiography for the
diagnosis of CAD. The prevalence of the 242T allele was not different in
149 patients with CAD compared to 103 patients with angiographically
normal coronary arteries. There were also no significant differences in
coronary epicardial or microvascular responses to acetylcholine or
sodium nitroprusside between the groups of patients with or without the
242T allele. In the overall study population of 252 patients, the CC
genotype was found in 39%, TC in 45%, and TT in 16%, giving a T allele
frequency of 0.34 in patients with normal coronary arteries and 0.42 in
CAD patients, with a trend in the direction opposite to that observed in
the Japanese population by Inoue et. al. (1998). The frequency of the T
allele was nearly 4 times higher in the U.S. population than in the
Japanese population.

- Reactive Oxygen Species Generation

Bedard et al. (2009) analyzed 7 CYBA polymorphisms and NOX2-dependent
reactive oxygen species (ROS) generation in 50 unrelated healthy
Caucasian individuals. The authors identified 11 haplotypes, which could
be grouped into 7 haplogroups. Only 1 haplogroup, designated 'C' and
containing the 214T-C, 521T-C (dbSNP rs1049254, 549C-T, V174A), and the
3-prime UTR 24G-A (dbSNP rs1049255, 640A-G) SNPs, had a significant
effect on ROS production, showing markedly reduced ROS generation
compared to other haplotypes. Although functional analysis demonstrated
significantly reduced reporter gene activity with the A allele of the
3-prime UTR SNP 24G-A compared to the G allele (p = 0.0055), haplotype
analysis indicated that the observed effect on ROS production was due to
the strong contribution of haplotype C. Bedard et al. (2009) suggested
that inconsistencies found in published reports might be due to the
analysis of individual SNPs rather than haplotypes.

ANIMAL MODEL

Nakano et al. (2008) found that induced-mutant nmf333 mice were
deficient in p22-phox protein due to a tyr121-to-his (Y121H) mutation in
the Cyba gene. Homozygous mutant mice showed chronic granulomatous
disease characterized by absence of superoxide production in phagocytes
and complete absence of NADPH oxidase activity. The mutant mice were
highly susceptible to fatal necrotizing B. cepacia pneumonia. In
addition, mutant mice showed a severe balance disorder associated with
complete absence of otoconia in the utricles and saccules of the inner
ear. Transgenic expression of wildtype Cyba rescued both phenotypes.
Studies on wildtype mice found Cyba expression in the endolymphatic
ducts of the embryonic inner ear, which decreased by postnatal day 12.
Based on these findings, Nakano et al. (2008) proposed that NOX activity
in the endolymph of the embryonic inner ear regulates local ionic
conditions and pH, which may favor the crystallization of calcium
carbonate and thereby promote the formation of otoconia. However, the
authors noted that balance disorders had not been described in humans
with CYBA-associated disease.

*FIELD* AV
.0001
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, 10-KB DEL

In a patient with autosomal recessive cytochrome b-negative CGD
(233690), whose parents were first cousins, Dinauer et al. (1990) found
homozygosity for a large deletion, approximately 10 kb, in the CYBA gene
that removed all but the extreme 5-prime coding sequence of the CYBA
gene. The patient had originally been reported by Baehner and Nathan
(1968).

.0002
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, 1-BP DEL, 272C

In a patient with autosomal recessive cytochrome b-negative CGD
(233690), Dinauer et al. (1990) found compound heterozygosity for 2
point mutations in the CYBA gene. One of them consisted of a single
nucleotide deletion, 272C, resulting in a frameshift. The other was a
297G-A change, resulting in and arg90-to-gln (R90Q) substitution
(608508.0003). The patient had previously been reported by Curnutte et
al. (1987).

.0003
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, ARG90GLN

See 608508.0002 and Dinauer et al. (1990).

de Boer et al. (1992) reported 3 patients with cytochrome b-negative CGD
(233690) from 1 family with first-cousin parents who were homozygous for
the R90Q mutation.

.0004
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, SER118ARG

In a patient with autosomal recessive cytochrome b-negative CGD
(233690), whose parents were second cousins, Dinauer et al. (1990) found
homozygosity for a 382C-A transversion, resulting in a ser118-to-arg
(S118R) substitution.

.0005
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, PRO156GLN

In a 22-year-old Caucasian female with autosomal recessive cytochrome
b-negative CGD (233690) who was the offspring of consanguineous parents,
Dinauer et al. (1991) identified a homozygous C-to-A transversion in the
CYBA gene that predicted a nonconservative pro156-to-gln (P156Q).

.0006
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, HIS94ARG

In a patient with autosomal recessive cytochrome b-negative CGD
(233690), offspring of first-cousin parents, de Boer et al. (1992) found
homozygosity for a 309A-G transition in the CYBA gene, resulting in a
nonconservative amino acid replacement, his94-to-arg (H94R).

.0007
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, IVS4DS, G-A, +1

In a patient with cytochrome b-negative CGD (233690) born of a
first-cousin marriage, de Boer et al. (1992) found homozygosity for the
absence of exon 4 in the CYBA gene. In this patient, a G-to-A transition
was found at position 1 of intron 4; hence, deletion of exon 4 was a
result of a splicing error.

.0008
CYBA POLYMORPHISM
CYBA, HIS72TYR, 242C-T

Parkos et al. (1988) identified a 242C-T polymorphism (dbSNP rs4673) in
exon 4 of the CYBA gene, leading to a his72-to-tyr (H72Y) substitution.
Data on its frequency in Japanese (Inoue et al., 1998) and U.S. (Li et
al., 1999) populations have been reported. Bedard et al. (2009) noted
that the 242C-T SNP is also referred to as 214T-C (Y72H) based on
numbering from the ATG codon.

.0009
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, GLN3TER

In a 33-year-old Japanese woman with cytochrome b-negative CGD (233690),
Yamada et al. (2000) demonstrated homozygosity for a nonsense mutation
in exon 1 of the CYBA gene.

.0010
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, GLY24ARG

In 2 presumably unrelated Japanese patients with mild cytochrome
b-negative CGD (233690), Yamada et al. (2000) identified homozygosity
for a 98G-A transition in exon 2 of the CYBA gene, resulting in a
gly24-to-arg (G24R) substitution. Since the mutation was identified in 2
such patients and since the parents in neither case were related, Yamada
et al. (2000) suggested that this may be a relatively common mutation in
the Japanese population.

.0011
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, 36-BP DEL

Stasia et al. (2002) used RT-PCR amplification and sequencing to
demonstrate a mutation in the p22-PHOX mRNA in a patient with autosomal
recessive cytochrome b-negative CGD (233690). The defect was a 179-bp
insertion associated with a 21-bp deletion of the beginning of exon 5 at
position 315 from the translation start codon of the cDNA. This defect
was also detected in the patient's parents. In the genomic DNA of the
patient, the molecular defect was a homozygous 36-bp deletion in the
linking sequence between intron 4 and exon 5. This genomic deletion
corresponded to 15 bp of the 3-prime extremity of intron 4 and 21 bp of
the beginning of exon 5 (the same deletion of exon 5 seen in the
corresponding mRNA). The splicing mRNA error was attributable to the
loss of the AG acceptor site of intron 4 and the utilization of a
cryptic splice site with an AG sequence at position 355-356 of intron 4.

.0012
GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE, CYTOCHROME b-NEGATIVE
CYBA, ALA125THR

In a patient with mild autosomal recessive cytochrome b-negative CGD
(233690), Teimourian et al. (2008) identified a homozygous 373G-A
transition in exon 6 of the CYBA gene, resulting in an ala125-to-thr
(A125T) substitution. The patient presented late at age 18 with
pneumonia and liver abscesses, even though there was no detectable p22
protein and no reactive oxygen species production.

*FIELD* SA
Parkos et al. (1987)
*FIELD* RF
1. Alexander, R. W.: Hypertension and the pathogenesis of atherosclerosis.
Oxidative stress and the mediation of arterial inflammatory response:
a new perspective. Hypertension 25: 155-161, 1995.

2. Baehner, R. L.; Nathan, D. G.: Quantitative nitroblue tetrazolium
test in chronic granulomatous disease. New Eng. J. Med. 278: 971-976,
1968.

3. Bedard, K.; Attar, H.; Bonnefont, J.; Jaquet, V.; Borel, C.; Plastre,
O.; Stasia, M.-J.; Antonarakis, S. E.; Krause, K.-H.: Three common
polymorphisms in the CYBA gene form a haplotype associated with decreased
ROS generation. Hum. Mutat. 30: 1123-1133, 2009.

4. Bu-Ghanim, H. N.; Casimir, C. M.; Povey, S.; Segal, A. W.: The
alpha subunit of cytochrome b(-245) mapped to chromosome 16. Genomics 8:
568-570, 1990.

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*FIELD* CN
Marla J. F. O'Neill - updated: 12/3/2009
Ada Hamosh - updated: 9/9/2009
Cassandra L. Kniffin - updated: 5/30/2008
Patricia A. Hartz - updated: 12/16/2004

*FIELD* CD
Cassandra L. Kniffin: 3/3/2004

*FIELD* ED
carol: 12/23/2009
wwang: 12/4/2009
terry: 12/3/2009
alopez: 9/14/2009
terry: 9/9/2009
alopez: 2/9/2009
wwang: 1/23/2009
ckniffin: 1/15/2009
wwang: 6/17/2008
ckniffin: 5/30/2008
mgross: 12/16/2004
carol: 3/12/2004
terry: 3/12/2004
ckniffin: 3/11/2004