RBCC Red Blood Cell Collection

CYBB (NOX2) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Cytochrome b-245 heavy chain; 1.-.-.- (CGD91-phox; Cytochrome b(558) subunit beta; Cytochrome b558 subunit beta; Heme-binding membrane glycoprotein gp91phox; NADPH oxidase 2; Neutrophil cytochrome b 91 kDa polypeptide; Superoxide-generating NADPH oxidase heavy chain subunit; gp91-1; gp91-phox; p22 phagocyte B-cytochrome)

UniProt P04839
ID CY24B_HUMAN Reviewed; 570 AA.
AC P04839; A8K138; Q2PP16;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Cytochrome b-245 heavy chain;
DE EC=1.-.-.-;
DE AltName: Full=CGD91-phox;
DE AltName: Full=Cytochrome b(558) subunit beta;
DE Short=Cytochrome b558 subunit beta;
DE AltName: Full=Heme-binding membrane glycoprotein gp91phox;
DE AltName: Full=NADPH oxidase 2;
DE AltName: Full=Neutrophil cytochrome b 91 kDa polypeptide;
DE AltName: Full=Superoxide-generating NADPH oxidase heavy chain subunit;
DE AltName: Full=gp91-1;
DE AltName: Full=gp91-phox;
DE AltName: Full=p22 phagocyte B-cytochrome;
GN Name=CYBB; Synonyms=NOX2;
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].
RX PubMed=2425263; DOI=10.1038/322032a0;
RA Royer-Pokora B., Kunkel L.M., Monaco A.P., Goff S.C., Newburger P.E.,
RA Baehner R.L., Cole F.S., Curnutte J.T., Orkin S.H.;
RT "Cloning the gene for an inherited human disorder -- chronic
RT granulomatous disease -- on the basis of its chromosomal location.";
RL Nature 322:32-38(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS CGD ASP-41 AND ARG-537,
RP AND VARIANTS ARG-364 AND GLU-517.
RX PubMed=12139950; DOI=10.1006/clim.2002.5230;
RA Jirapongsananuruk O., Niemela J.E., Malech H.L., Fleisher T.A.;
RT "CYBB mutation analysis in X-linked chronic granulomatous disease.";
RL Clin. Immunol. 104:73-76(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-135.
RX PubMed=3600768; DOI=10.1038/327717a0;
RA Dinauer M.C., Orkin S.H., Brown R., Jesaitis A.J., Parkos C.A.;
RT "The glycoprotein encoded by the X-linked chronic granulomatous
RT disease locus is a component of the neutrophil cytochrome b complex.";
RL Nature 327:717-720(1987).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 233-267.
RC TISSUE=Peripheral blood;
RX PubMed=9790760; DOI=10.1006/geno.1998.5510;
RA Kumatori A., Faizunnessa N.N., Suzuki S., Moriuchi T., Kurozumi H.,
RA Nakamura M.;
RT "Nonhomologous recombination between the cytochrome b558 heavy chain
RT gene (CYBB) and LINE-1 causes an X-linked chronic granulomatous
RT disease.";
RL Genomics 53:123-128(1998).
RN [9]
RP PROTEIN SEQUENCE OF 2-44, AND SUBUNIT.
RX PubMed=3600769; DOI=10.1038/327720a0;
RA Teahan C., Rowe P., Parker P., Totty N., Segal A.W.;
RT "The X-linked chronic granulomatous disease gene codes for the beta-
RT chain of cytochrome b-245.";
RL Nature 327:720-721(1987).
RN [10]
RP CHARACTERIZATION AS A PROTON CHANNEL.
RX PubMed=10578014;
RA Henderson L.M., Meech R.W.;
RT "Evidence that the product of the human X-linked CGD gene, gp91-phox,
RT is a voltage-gated H(+) pathway.";
RL J. Gen. Physiol. 114:771-786(1999).
RN [11]
RP SUBUNIT, PHOSPHORYLATION, AND TISSUE SPECIFICITY.
RX PubMed=19028840; DOI=10.1096/fj.08-114553;
RA Raad H., Paclet M.H., Boussetta T., Kroviarski Y., Morel F.,
RA Quinn M.T., Gougerot-Pocidalo M.A., Dang P.M., El-Benna J.;
RT "Regulation of the phagocyte NADPH oxidase activity: phosphorylation
RT of gp91phox/NOX2 by protein kinase C enhances its diaphorase activity
RT and binding to Rac2, p67phox, and p47phox.";
RL FASEB J. 23:1011-1022(2009).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-132; ASN-149 AND ASN-240,
RP AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [13]
RP STRUCTURE BY NMR OF 556-570 IN COMPLEX WITH NCF1, AND INTERACTION WITH
RP NCF1.
RX PubMed=9224653;
RA Adams E.R., Dratz E.A., Gizachew D., Deleo F.R., Yu L., Volpp B.D.,
RA Vlases M., Jesaitis A.J., Quinn M.T.;
RT "Interaction of human neutrophil flavocytochrome b with cytosolic
RT proteins: transferred-NOESY NMR studies of a gp91phox C-terminal
RT peptide bound to p47phox.";
RL Biochem. J. 325:249-257(1997).
RN [14]
RP VARIANT CGD HIS-415.
RX PubMed=2556453; DOI=10.1172/JCI114393;
RA Dinauer M.C., Curnutte J.T., Rosen H.R., Orkin S.H.;
RT "A missense mutation in the neutrophil cytochrome b heavy chain in
RT cytochrome-positive X-linked chronic granulomatous disease.";
RL J. Clin. Invest. 84:2012-2016(1989).
RN [15]
RP VARIANTS CGD ARG-101; THR-156; TYR-209; SER-244 AND ALA-389.
RX PubMed=1710153;
RA Bolscher B.G.J.M., de Boer M., de Klein A., Weening R.S., Roos D.;
RT "Point mutations in the beta-subunit of cytochrome b558 leading to X-
RT linked chronic granulomatous disease.";
RL Blood 77:2482-2487(1991).
RN [16]
RP VARIANT CGD GLU-57.
RX PubMed=8101486; DOI=10.1007/BF01955051;
RA Ariga T., Sakiyama Y., Tomizawa K., Imajoh-Ohmi S., Kanegasaki S.,
RA Matsumoto S.;
RT "A newly recognized point mutation in the cytochrome b558 heavy chain
RT gene replacing alanine57 by glutamic acid, in a patient with
RT cytochrome b positive X-linked chronic granulomatous disease.";
RL Eur. J. Pediatr. 152:469-472(1993).
RN [17]
RP VARIANT CGD HIS-339.
RX PubMed=7927345; DOI=10.1007/BF00201609;
RA Ariga T., Sakiyama Y., Matsumoto S.;
RT "Two novel point mutations in the cytochrome b 558 heavy chain gene,
RT detected in two Japanese patients with X-linked chronic granulomatous
RT disease.";
RL Hum. Genet. 94:441-441(1994).
RN [18]
RP VARIANT CGD GLY-500.
RX PubMed=8182143; DOI=10.1172/JCI117207;
RA Leusen J.H.W., de Boer M., Bolscher B.G.J.M., Hilarius P.M.,
RA Weening R.S., Ochs H.D., Roos D., Verhoeven A.J.;
RT "A point mutation in gp91-phox of cytochrome b558 of the human NADPH
RT oxidase leading to defective translocation of the cytosolic proteins
RT p47-phox and p67-phox.";
RL J. Clin. Invest. 93:2120-2126(1994).
RN [19]
RP VARIANTS CGD ILE-205; PHE-215 DEL AND GLN-342.
RX PubMed=8916969;
RA Hui Y.F., Chan S.Y., Lau Y.L.;
RT "Identification of mutations in seven Chinese patients with X-linked
RT chronic granulomatous disease.";
RL Blood 88:4021-4028(1996).
RN [20]
RP ERRATUM.
RA Hui Y.F., Chan S.Y., Lau Y.L.;
RL Blood 89:1843-1843(1996).
RN [21]
RP VARIANT CGD PHE-215 DEL.
RX PubMed=9111587;
RA Jendrossek V., Ritzel A., Neubauer B., Heyden S., Gahr M.;
RT "An in-frame triplet deletion within the gp91-phox gene in an adult X-
RT linked chronic granulomatous disease patient with residual NADPH-
RT oxidase activity.";
RL Eur. J. Haematol. 58:78-85(1997).
RN [22]
RP VARIANTS CGD ARG-20; SER-54; ARG-59; ARG-119; THR-156; GLN-209;
RP ASN-222; ARG-222; TYR-222; LEU-223; ARG-244; LYS-309; LYS-315 DEL;
RP GLU-322; PHE-325; PRO-333; HIS-339; PRO-356; ARG-405; GLU-408;
RP ARG-408; HIS-415; LEU-415; PRO-422; ARG-453; CYS-516; ASP-534 AND
RP ARG-537.
RX PubMed=9585602; DOI=10.1086/301874;
RA Rae J., Newburger P.E., Dinauer M.C., Noack D., Hopkins P.J.,
RA Kuruto R., Curnutte J.T.;
RT "X-linked chronic granulomatous disease: mutations in the CYBB gene
RT encoding the gp91-phox component of respiratory-burst oxidase.";
RL Am. J. Hum. Genet. 62:1320-1331(1998).
RN [23]
RP VARIANT CGD TYR-101.
RX PubMed=9856476; DOI=10.1007/s004390050836;
RA Tsuda M., Kaneda M., Sakiyama T., Inana I., Owada M., Kiryu C.,
RA Shiraishi T., Kakinuma K.;
RT "A novel mutation at a probable heme-binding ligand in neutrophil
RT cytochrome b558 in atypical X-linked chronic granulomatous disease.";
RL Hum. Genet. 103:377-381(1998).
RN [24]
RP VARIANTS CGD ARG-179 AND 298-THR--THR-302 DEL.
RX PubMed=9794433;
RA Dusi S., Nadalini K.A., Donini M., Zentilin L., Wientjes F.B.,
RA Roos D., Giacca M., Rossi F.;
RT "Nicotinamide-adenine dinucleotide phosphate oxidase assembly and
RT activation in EBV-transformed B lymphoblastoid cell lines of normal
RT and chronic granulomatous disease patients.";
RL J. Immunol. 161:4968-4974(1998).
RN [25]
RP VARIANTS CGD MET-54; ASP-55; GLU-57; HIS-339 AND PHE-344.
RX PubMed=9667376; DOI=10.1203/00006450-199807000-00014;
RA Ariga T., Furuta H., Cho K., Sakiyama Y.;
RT "Genetic analysis of 13 families with X-linked chronic granulomatous
RT disease reveals a low proportion of sporadic patients and a high
RT proportion of sporadic carriers.";
RL Pediatr. Res. 44:85-92(1998).
RN [26]
RP VARIANTS CGD PHE-193; ARG-222; TYR-338; HIS-339 AND PRO-546, AND
RP VARIANT ARG-364.
RX PubMed=10089913; DOI=10.1016/S0301-472X(98)00024-1;
RA Roesler J., Heyden S., Burdelski M., Schaefer H., Kreth H.-W.,
RA Lehmann R., Paul D., Marzahn J., Gahr M., Roesen-Wolff A.;
RT "Uncommon missense and splice mutations and resulting biochemical
RT phenotypes in German patients with X-linked chronic granulomatous
RT disease.";
RL Exp. Hematol. 27:505-511(1999).
RN [27]
RP VARIANTS CGD VAL-225 AND TYR-244.
RX PubMed=9888386;
RX DOI=10.1002/(SICI)1098-1004(1999)13:1<29::AID-HUMU3>3.0.CO;2-X;
RA Patino P.J., Perez J.E., Lopez J.A., Condino-Neto A., Grumach A.S.,
RA Botero J.H., Curnutte J.T., Garcia de Olarte D.;
RT "Molecular analysis of chronic granulomatous disease caused by defects
RT in gp91-phox.";
RL Hum. Mutat. 13:29-37(1999).
RN [28]
RP VARIANTS CGD MET-54; ASP-55; GLU-57; TYR-101; ARG-209; GLY-224;
RP LYS-309; TYR-338; HIS-339; PHE-344; GLU-389; PRO-420 AND ARG-516.
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 [29]
RP VARIANTS CGD 54-ARG-ALA-55 DEL; TRP-59; PRO-307 AND ARG-505.
RX PubMed=11462241; DOI=10.1002/humu.1166;
RA Gerard B., El Benna J., Alcain F., Gougerot-Pocidalo M.-A.,
RA Grandchamp B., Chollet-Martin S.;
RT "Characterization of 11 novel mutations in the X-linked chronic
RT granulomatous disease (CYBB gene).";
RL Hum. Mutat. 18:163-163(2001).
RN [30]
RP VARIANTS CGD ASN-303 AND ARG-304.
RX PubMed=11997083; DOI=10.1016/S0925-4439(01)00110-7;
RA Stasia M.J., Lardy B., Maturana A., Rousseau P., Martel C.,
RA Bordigoni P., Demaurex N., Morel F.;
RT "Molecular and functional characterization of a new X-linked chronic
RT granulomatous disease variant (X91+) case with a double missense
RT mutation in the cytosolic gp91phox C-terminal tail.";
RL Biochim. Biophys. Acta 1586:316-330(2002).
RN [31]
RP CHARACTERIZATION OF VARIANTS CGD ASN-303 AND ARG-304.
RX PubMed=15338276; DOI=10.1007/s00439-004-1173-z;
RA Bionda C., Li X.J., van Bruggen R., Eppink M., Roos D., Morel F.,
RA Stasia M.-J.;
RT "Functional analysis of two-amino acid substitutions in gp91 phox in a
RT patient with X-linked flavocytochrome b558-positive chronic
RT granulomatous disease by means of transgenic PLB-985 cells.";
RL Hum. Genet. 115:418-427(2004).
RN [32]
RP VARIANT CGD ARG-408.
RX PubMed=18773283; DOI=10.1007/s10875-008-9243-y;
RA Bakri F.G., Martel C., Khuri-Bulos N., Mahafzah A., El-Khateeb M.S.,
RA Al-Wahadneh A.M., Hayajneh W.A., Hamamy H.A., Maquet E., Molin M.,
RA Stasia M.J.;
RT "First report of clinical, functional, and molecular investigation of
RT chronic granulomatous disease in nine Jordanian families.";
RL J. Clin. Immunol. 29:215-230(2009).
RN [33]
RP VARIANTS AMCBX2 PRO-178 AND PRO-231.
RX PubMed=21278736; DOI=10.1038/ni.1992;
RA Bustamante J., Arias A.A., Vogt G., Picard C., Galicia L.B.,
RA Prando C., Grant A.V., Marchal C.C., Hubeau M., Chapgier A.,
RA de Beaucoudrey L., Puel A., Feinberg J., Valinetz E., Janniere L.,
RA Besse C., Boland A., Brisseau J.M., Blanche S., Lortholary O.,
RA Fieschi C., Emile J.F., Boisson-Dupuis S., Al-Muhsen S., Woda B.,
RA Newburger P.E., Condino-Neto A., Dinauer M.C., Abel L., Casanova J.L.;
RT "Germline CYBB mutations that selectively affect macrophages in
RT kindreds with X-linked predisposition to tuberculous mycobacterial
RT disease.";
RL Nat. Immunol. 12:213-221(2011).
RN [34]
RP VARIANTS CGD ASP-488 AND GLU-500.
RX PubMed=22125116; DOI=10.1002/humu.22003;
RA Boog B., Quach A., Costabile M., Smart J., Quinn P., Singh H.,
RA Gold M., Booker G., Choo S., Hii C.S., Ferrante A.;
RT "Identification and functional characterization of two novel mutations
RT in the alpha-helical loop (residues 484-503) of CYBB/gp91(phox)
RT resulting in the rare X91(+) variant of chronic granulomatous
RT disease.";
RL Hum. Mutat. 33:471-475(2012).
CC -!- FUNCTION: Critical component of the membrane-bound oxidase of
CC phagocytes that generates superoxide. It is the terminal component
CC of a respiratory chain that transfers single electrons from
CC cytoplasmic NADPH across the plasma membrane to molecular oxygen
CC on the exterior. Also functions as a voltage-gated proton channel
CC that mediates the H(+) currents of resting phagocytes. It
CC participates in the regulation of cellular pH and is blocked by
CC zinc.
CC -!- COFACTOR: FAD (Probable).
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.
CC Interacts with calprotectin (S100A8/9).
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Detected in neutrophils (at protein level).
CC -!- PTM: Glycosylated.
CC -!- PTM: Phosphorylated on Ser and Thr residues.
CC -!- DISEASE: Granulomatous disease, chronic, X-linked (CGD)
CC [MIM:306400]: A disorder characterized by the inability of
CC neutrophils and phagocytes to kill microbes that they have
CC ingested. Patients suffer from life-threatening bacterial/fungal
CC infections. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- DISEASE: Mycobacteriosis atypical X-linked 2 (AMCBX2)
CC [MIM:300645]: A rare condition characterized by predisposition to
CC illness caused by moderately virulent mycobacterial species, such
CC as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-
CC tuberculous mycobacteria, and by the more virulent Mycobacterium
CC tuberculosis. Other microorganisms rarely cause severe clinical
CC disease in individuals with susceptibility to mycobacterial
CC infections. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 FAD-binding FR-type domain.
CC -!- SIMILARITY: Contains 1 ferric oxidoreductase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA27635.1; Type=Erroneous initiation;
CC Sequence=CAA29327.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=CYBBbase; Note=CYBB deficiency database;
CC URL="http://bioinf.uta.fi/CYBBbase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CYBB";
CC -!- WEB RESOURCE: Name=Mendelian genes cytochrome b-245, beta
CC polypeptide (CYBB); Note=Leiden Open Variation Database (LOVD);
CC URL="http://www.lovd.nl/CYBB";
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DR EMBL; X04011; CAA27635.1; ALT_INIT; mRNA.
DR EMBL; AF469769; AAL76082.1; -; Genomic_DNA.
DR EMBL; AF469757; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469758; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469759; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469760; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469761; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469762; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469763; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469764; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469765; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469766; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469767; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; AF469768; AAL76082.1; JOINED; Genomic_DNA.
DR EMBL; DQ314869; ABC40728.1; -; Genomic_DNA.
DR EMBL; AK289753; BAF82442.1; -; mRNA.
DR EMBL; CH471141; EAW59453.1; -; Genomic_DNA.
DR EMBL; BC032720; AAH32720.1; -; mRNA.
DR EMBL; X05895; CAA29327.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AB013904; BAA34183.1; -; Genomic_DNA.
DR PIR; S70773; S70773.
DR RefSeq; NP_000388.2; NM_000397.3.
DR UniGene; Hs.292356; -.
DR PDB; 3A1F; X-ray; 2.00 A; A=385-570.
DR PDBsum; 3A1F; -.
DR ProteinModelPortal; P04839; -.
DR SMR; P04839; 385-570.
DR DIP; DIP-42005N; -.
DR IntAct; P04839; 1.
DR MINT; MINT-191276; -.
DR STRING; 9606.ENSP00000367851; -.
DR BindingDB; P04839; -.
DR ChEMBL; CHEMBL1287627; -.
DR PeroxiBase; 5962; HsNOx02.
DR TCDB; 5.B.1.1.1; the phagocyte (gp91(phox)) nadph oxidase family.
DR PhosphoSite; P04839; -.
DR DMDM; 115211; -.
DR PaxDb; P04839; -.
DR PeptideAtlas; P04839; -.
DR PRIDE; P04839; -.
DR DNASU; 1536; -.
DR Ensembl; ENST00000378588; ENSP00000367851; ENSG00000165168.
DR Ensembl; ENST00000596392; ENSP00000468868; ENSG00000268765.
DR GeneID; 1536; -.
DR KEGG; hsa:1536; -.
DR UCSC; uc004ddr.2; human.
DR CTD; 1536; -.
DR GeneCards; GC0XP037639; -.
DR HGNC; HGNC:2578; CYBB.
DR HPA; CAB032510; -.
DR MIM; 300481; gene.
DR MIM; 300645; phenotype.
DR MIM; 306400; phenotype.
DR neXtProt; NX_P04839; -.
DR Orphanet; 379; Chronic granulomatous disease.
DR Orphanet; 319623; X-linked mendelian susceptibility to mycobacterial diseases due to CYBB deficiency.
DR PharmGKB; PA27076; -.
DR eggNOG; NOG287712; -.
DR HOGENOM; HOG000216669; -.
DR HOVERGEN; HBG003760; -.
DR InParanoid; P04839; -.
DR KO; K08008; -.
DR OMA; VFIQCPS; -.
DR PhylomeDB; P04839; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR GeneWiki; CYBB; -.
DR GenomeRNAi; 1536; -.
DR NextBio; 6353; -.
DR PRO; PR:P04839; -.
DR ArrayExpress; P04839; -.
DR Bgee; P04839; -.
DR CleanEx; HS_CYBB; -.
DR Genevestigator; P04839; -.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0043020; C:NADPH oxidase complex; IDA:BHF-UCL.
DR GO; GO:0030670; C:phagocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IMP:BHF-UCL.
DR GO; GO:0020037; F:heme binding; IMP:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016175; F:superoxide-generating NADPH oxidase activity; TAS:BHF-UCL.
DR GO; GO:0005244; F:voltage-gated ion channel 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:0050665; P:hydrogen peroxide biosynthetic process; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; IMP:BHF-UCL.
DR GO; GO:0051701; P:interaction with host; TAS:Reactome.
DR GO; GO:0090382; P:phagosome maturation; TAS:Reactome.
DR GO; GO:0045730; P:respiratory burst; IMP:BHF-UCL.
DR GO; GO:0042554; P:superoxide anion generation; IDA:BHF-UCL.
DR InterPro; IPR000778; Cyt_b245_heavy_chain.
DR InterPro; IPR013112; FAD-bd_8.
DR InterPro; IPR017927; Fd_Rdtase_FAD-bd.
DR InterPro; IPR013130; Fe3_Rdtase_TM_dom.
DR InterPro; IPR013121; Fe_red_NAD-bd_6.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR Pfam; PF08022; FAD_binding_8; 1.
DR Pfam; PF01794; Ferric_reduct; 1.
DR Pfam; PF08030; NAD_binding_6; 1.
DR PRINTS; PR00466; GP91PHOX.
DR SUPFAM; SSF63380; SSF63380; 1.
DR PROSITE; PS51384; FAD_FR; 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; FAD; Flavoprotein; Glycoprotein; Heme;
KW Ion channel; Ion transport; Iron; Membrane; Metal-binding; NADP;
KW Oxidoreductase; Phosphoprotein; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 570 Cytochrome b-245 heavy chain.
FT /FTId=PRO_0000210145.
FT TOPO_DOM 2 8 Cytoplasmic (Potential).
FT TRANSMEM 9 29 Helical; (Potential).
FT TOPO_DOM 30 48 Extracellular (Potential).
FT TRANSMEM 49 69 Helical; (Potential).
FT TOPO_DOM 70 102 Cytoplasmic (Potential).
FT TRANSMEM 103 123 Helical; (Potential).
FT TOPO_DOM 124 169 Extracellular (Potential).
FT TRANSMEM 170 190 Helical; (Potential).
FT TOPO_DOM 191 200 Cytoplasmic (Potential).
FT TRANSMEM 201 221 Helical; (Potential).
FT TOPO_DOM 222 261 Extracellular (Potential).
FT TRANSMEM 262 282 Helical; (Potential).
FT TOPO_DOM 283 570 Cytoplasmic (Potential).
FT DOMAIN 54 286 Ferric oxidoreductase.
FT DOMAIN 287 397 FAD-binding FR-type.
FT NP_BIND 338 344 FAD (Potential).
FT METAL 101 101 Iron (heme axial ligand) (Probable).
FT METAL 115 115 Iron (heme axial ligand) (Probable).
FT METAL 209 209 Iron (heme axial ligand) (Probable).
FT METAL 222 222 Iron (heme axial ligand) (Probable).
FT CARBOHYD 132 132 N-linked (GlcNAc...).
FT CARBOHYD 149 149 N-linked (GlcNAc...).
FT CARBOHYD 240 240 N-linked (GlcNAc...).
FT VARIANT 18 18 W -> C (in CGD).
FT /FTId=VAR_047264.
FT VARIANT 20 20 G -> R (in CGD; dbSNP:rs151344455).
FT /FTId=VAR_007873.
FT VARIANT 41 41 Y -> D (in CGD; dbSNP:rs151344453).
FT /FTId=VAR_025613.
FT VARIANT 54 55 Missing (in CGD).
FT /FTId=VAR_047265.
FT VARIANT 54 54 R -> M (in CGD; dbSNP:rs151344479).
FT /FTId=VAR_025614.
FT VARIANT 54 54 R -> S (in CGD; dbSNP:rs151344456).
FT /FTId=VAR_007874.
FT VARIANT 55 55 A -> D (in CGD; dbSNP:rs151344480).
FT /FTId=VAR_025615.
FT VARIANT 57 57 A -> E (in CGD; dbSNP:rs151344481).
FT /FTId=VAR_008845.
FT VARIANT 59 59 C -> R (in CGD; dbSNP:rs151344457).
FT /FTId=VAR_007875.
FT VARIANT 59 59 C -> W (in CGD; dbSNP:rs151344488).
FT /FTId=VAR_047266.
FT VARIANT 101 101 H -> R (in CGD; dbSNP:rs137854591).
FT /FTId=VAR_002432.
FT VARIANT 101 101 H -> Y (in CGD; dbSNP:rs137854594).
FT /FTId=VAR_007876.
FT VARIANT 119 119 H -> R (in CGD; dbSNP:rs151344458).
FT /FTId=VAR_007877.
FT VARIANT 156 156 A -> T (in CGD; dbSNP:rs137854590).
FT /FTId=VAR_002433.
FT VARIANT 178 178 T -> P (in AMCBX2; dbSNP:rs151344497).
FT /FTId=VAR_065365.
FT VARIANT 179 179 G -> R (in CGD; dbSNP:rs151344491).
FT /FTId=VAR_047267.
FT VARIANT 193 193 S -> F (in CGD; dbSNP:rs151344493).
FT /FTId=VAR_047268.
FT VARIANT 205 205 F -> I (in CGD; dbSNP:rs151344496).
FT /FTId=VAR_047269.
FT VARIANT 209 209 H -> Q (in CGD; dbSNP:rs151344459).
FT /FTId=VAR_007878.
FT VARIANT 209 209 H -> R (in CGD; dbSNP:rs151344482).
FT /FTId=VAR_025616.
FT VARIANT 209 209 H -> Y (in CGD; dbSNP:rs137854587).
FT /FTId=VAR_002434.
FT VARIANT 215 215 Missing (in CGD).
FT /FTId=VAR_007879.
FT VARIANT 222 222 H -> N (in CGD; dbSNP:rs151344460).
FT /FTId=VAR_007880.
FT VARIANT 222 222 H -> R (in CGD; dbSNP:rs151344462).
FT /FTId=VAR_007881.
FT VARIANT 222 222 H -> Y (in CGD; dbSNP:rs151344460).
FT /FTId=VAR_007882.
FT VARIANT 223 223 G -> L (in CGD; requires 2 nucleotide
FT substitutions; dbSNP:rs151344463 and
FT dbSNP:rs151344464).
FT /FTId=VAR_007883.
FT VARIANT 224 224 A -> G (in CGD; dbSNP:rs151344483).
FT /FTId=VAR_025617.
FT VARIANT 225 225 E -> V (in CGD; dbSNP:rs151344494).
FT /FTId=VAR_002435.
FT VARIANT 231 231 Q -> P (in AMCBX2; dbSNP:rs151344498).
FT /FTId=VAR_065366.
FT VARIANT 244 244 C -> R (in CGD; dbSNP:rs151344465).
FT /FTId=VAR_007884.
FT VARIANT 244 244 C -> S (in CGD; dbSNP:rs137854589).
FT /FTId=VAR_002436.
FT VARIANT 244 244 C -> Y (in CGD; dbSNP:rs137854589).
FT /FTId=VAR_002437.
FT VARIANT 298 302 Missing (in CGD).
FT /FTId=VAR_047270.
FT VARIANT 303 303 H -> N (in CGD; completely inhibits NADPH
FT oxidase activity; NADPH oxidase assembly
FT is abolished; dbSNP:rs137854595).
FT /FTId=VAR_016880.
FT VARIANT 304 304 P -> R (in CGD; reduces NADPH oxidase
FT activity to 4% of wild-type;
FT translocation to the membrane of the
FT phagosome is only attenuated;
FT dbSNP:rs137854596).
FT /FTId=VAR_016881.
FT VARIANT 307 307 T -> P (in CGD; dbSNP:rs151344489).
FT /FTId=VAR_047271.
FT VARIANT 309 309 E -> K (in CGD; dbSNP:rs151344466).
FT /FTId=VAR_007885.
FT VARIANT 315 315 Missing (in CGD).
FT /FTId=VAR_047272.
FT VARIANT 322 322 G -> E (in CGD; dbSNP:rs151344467).
FT /FTId=VAR_007886.
FT VARIANT 325 325 I -> F (in CGD; dbSNP:rs151344468).
FT /FTId=VAR_007887.
FT VARIANT 333 333 S -> P (in CGD; dbSNP:rs151344469).
FT /FTId=VAR_007888.
FT VARIANT 338 338 H -> Y (in CGD; dbSNP:rs151344484).
FT /FTId=VAR_025618.
FT VARIANT 339 339 P -> H (in CGD; dbSNP:rs151344470).
FT /FTId=VAR_002438.
FT VARIANT 342 342 L -> Q (in CGD; dbSNP:rs151344495).
FT /FTId=VAR_047273.
FT VARIANT 344 344 S -> F (in CGD; dbSNP:rs151344485).
FT /FTId=VAR_025619.
FT VARIANT 356 356 R -> P (in CGD; dbSNP:rs151344471).
FT /FTId=VAR_007889.
FT VARIANT 364 364 G -> R (in dbSNP:rs141756032).
FT /FTId=VAR_025620.
FT VARIANT 389 389 G -> A (in CGD; dbSNP:rs137854586).
FT /FTId=VAR_002439.
FT VARIANT 389 389 G -> E (in CGD; dbSNP:rs137854586).
FT /FTId=VAR_025621.
FT VARIANT 405 405 M -> R (in CGD; dbSNP:rs151344472).
FT /FTId=VAR_007890.
FT VARIANT 408 408 G -> E (in CGD; dbSNP:rs151344474).
FT /FTId=VAR_007891.
FT VARIANT 408 408 G -> R (in CGD; dbSNP:rs151344473).
FT /FTId=VAR_007892.
FT VARIANT 415 415 P -> H (in CGD; dbSNP:rs137854585).
FT /FTId=VAR_002440.
FT VARIANT 415 415 P -> L (in CGD; dbSNP:rs137854585).
FT /FTId=VAR_007893.
FT VARIANT 420 420 L -> P (in CGD; dbSNP:rs151344486).
FT /FTId=VAR_025622.
FT VARIANT 422 422 S -> P (in CGD; dbSNP:rs151344475).
FT /FTId=VAR_007894.
FT VARIANT 453 453 W -> R (in CGD; dbSNP:rs151344476).
FT /FTId=VAR_007895.
FT VARIANT 472 472 G -> S (in dbSNP:rs13306300).
FT /FTId=VAR_047274.
FT VARIANT 488 488 A -> D (in CGD).
FT /FTId=VAR_068012.
FT VARIANT 500 500 D -> E (in CGD).
FT /FTId=VAR_068013.
FT VARIANT 500 500 D -> G (in CGD; dbSNP:rs137854593).
FT /FTId=VAR_002441.
FT VARIANT 505 505 L -> R (in CGD; dbSNP:rs151344490).
FT /FTId=VAR_047275.
FT VARIANT 516 516 W -> C (in CGD; dbSNP:rs151344477).
FT /FTId=VAR_007896.
FT VARIANT 516 516 W -> R (in CGD; dbSNP:rs151344487).
FT /FTId=VAR_025623.
FT VARIANT 517 517 D -> E (in dbSNP:rs151344452).
FT /FTId=VAR_025624.
FT VARIANT 534 534 V -> D (in CGD; dbSNP:rs151344478).
FT /FTId=VAR_007897.
FT VARIANT 537 537 C -> R (in CGD; dbSNP:rs151344454).
FT /FTId=VAR_007898.
FT VARIANT 546 546 L -> P (in CGD; dbSNP:rs151344492).
FT /FTId=VAR_047276.
FT CONFLICT 14 14 V -> A (in Ref. 1 and 5).
FT HELIX 393 398
FT STRAND 401 409
FT HELIX 410 412
FT HELIX 413 429
FT STRAND 438 446
FT TURN 448 451
FT HELIX 452 467
FT STRAND 473 480
FT STRAND 509 512
FT HELIX 516 526
FT STRAND 531 538
FT HELIX 540 552
FT STRAND 562 566
SQ SEQUENCE 570 AA; 65336 MW; 7E84051BD4000CE3 CRC64;
MGNWAVNEGL SIFVILVWLG LNVFLFVWYY RVYDIPPKFF YTRKLLGSAL ALARAPAACL
NFNCMLILLP VCRNLLSFLR GSSACCSTRV RRQLDRNLTF HKMVAWMIAL HSAIHTIAHL
FNVEWCVNAR VNNSDPYSVA LSELGDRQNE SYLNFARKRI KNPEGGLYLA VTLLAGITGV
VITLCLILII TSSTKTIRRS YFEVFWYTHH LFVIFFIGLA IHGAERIVRG QTAESLAVHN
ITVCEQKISE WGKIKECPIP QFAGNPPMTW KWIVGPMFLY LCERLVRFWR SQQKVVITKV
VTHPFKTIEL QMKKKGFKME VGQYIFVKCP KVSKLEWHPF TLTSAPEEDF FSIHIRIVGD
WTEGLFNACG CDKQEFQDAW KLPKIAVDGP FGTASEDVFS YEVVMLVGAG IGVTPFASIL
KSVWYKYCNN ATNLKLKKIY FYWLCRDTHA FEWFADLLQL LESQMQERNN AGFLSYNIYL
TGWDESQANH FAVHHDEEKD VITGLKQKTL YGRPNWDNEF KTIASQHPNT RIGVFLCGPE
ALAETLSKQS ISNSESGPRG VHFIFNKENF
//

MIM 300481
*RECORD*
*FIELD* NO
300481
*FIELD* TI
*300481 CYTOCHROME b(-245), BETA SUBUNIT; CYBB
;;CYTOCHROME b(558), BETA SUBUNIT;;
read morep91-PHOX;;
NADPH OXIDASE 2; NOX2;;
GP91-1
*FIELD* TX

DESCRIPTION

Cytochrome b(-245) is a heterodimer of the p91-phox beta polypeptide
(CYBB) (phox for phagocyte oxidase) and a smaller p22-phox alpha
polypeptide (CYBA; 608508).

Cytochrome b(-245) is an essential component of phagocytic
NADPH-oxidase, a membrane-bound enzyme complex that generates large
quantities of microbicidal superoxide and other oxidants upon
activation. Active NADPH oxidase also requires several cytosolic
proteins, including p47-phox (608512), p67-phox (233710), p40-phox
(601488), and a GTP-binding protein, either rac1 (602048) in macrophages
or rac2 (602049) in neutrophils (Leusen et al., 1994). This cytochrome b
has a very low midpoint potential of -245 mV and a characteristic
spectrophotometric absorption band at 558 nm, and is also known as
cytochrome b(558). The CYBB gene product has also been referred to as
cgd91-phox (Schapiro et al., 1991).

CLONING

In what may be the first example of 'reverse genetics,' later more
appropriately termed 'positional cloning,' Royer-Pokora et al. (1986)
cloned the gene that is abnormal in X-linked chronic granulomatous
disease (CGD; 306400) without reference to a specific protein. This was
done by relying on the chromosomal map position of the gene and was, in
effect, a byproduct of the chromosome walking experiments aimed at
characterizing the DMD locus. From human leukemic cells treated with
dimethylformamide, which induces the NADPH-oxidase system and other
constituents of granulocytic differentiation, Royer-Pokora et al. (1986)
isolated a cDNA that was subjected to subtractive hybridization with RNA
from a cell line of a patient with deletion of the CGD/DMD complex in
Xp21. The subtracted radiolabeled cDNA was hybridized to a Southern blot
of Xp21 bacteriophage clones. Two overlapping clones (pERT 379) showed
hybridization. The transcript of the gene was expressed in the
phagocytic lineage of hematopoietic cells and was absent or structurally
abnormal in 4 patients with CGD. The nucleotide sequence of cDNA clones
predicted a polypeptide of at least 468 amino acids with no homology to
previously described proteins. Specifically, cytochrome b was excluded.
Although a consistent finding in X-linked CGD is absence of the heme
spectrum derived from cytochrome b, the authors suggested that the
deficiency may be secondary to the primary genetic abnormality.

Dinauer et al. (1987) raised antibodies to a synthetic peptide derived
from the cDNA sequence of the putative CGD gene. Western blot analysis
detected a neutrophil protein of relative molecular mass 90 kD that was
absent in CGD patients. Antisera also reacted with the larger component
of cytochrome b purified from neutrophil plasma membranes as a complex
of glycosylated 90-kD and nonglycosylated 22-kD polypeptides. Dinauer et
al. (1987) proposed that one of the critical roles of the CGD protein in
vivo is to interact with the 22-kD polypeptide to form a functional
cytochrome b complex.

Cytochrome b(-245) is a heterodimer composed of an alpha chain of
relative molecular mass 23 kD and a beta chain of 76 to 82 kD. Teahan et
al. (1987) purified the beta-chain protein of the cytochrome and
sequenced 43 amino acids from the N terminus. Almost complete homology
was obtained between this sequence and that of the complementary
nucleotides 19-147 of the sequence of the CGD gene. Teahan et al. (1987)
pointed to work indicating that cytochrome b(-245) is missing from the
cells of CGD patients; neither the alpha nor the beta subunits are
detectable in neutrophils from CGD patients. Parkos et al. (1987)
demonstrated that the purified cytochrome b from human granulocyte
plasma membrane is comprised of 2 polypeptides of relative molecular
masses 91 kD and 22 kD, and noted that the 91-kD protein is affected in
X-linked CGD.

Orkin (1987) stated that unraveling the genetic basis of X-linked CGD
was dependent not only on gene cloning based on chromosomal map position
and preparation of antisera directed to a known protein, but also on the
existence of complementary biochemical data which identified the unknown
product as a component of the cytochrome b complex.

GENE FUNCTION

Jackson et al. (2004) reported that activated mouse T cells deficient in
either gp91-phox or p47-phox showed enhanced activation of Erk (see
MAPK3; 601795) and Mek (see MAP2K1; 176872), diminished expression of
phagocyte-type NADPH oxidase, and a relative increase in Th1-type
cytokine secretion. They suggested that similar alterations may be found
in patients with chronic granulomatous disease.

Dendritic cells (DCs) present antigens from pathogens or infected cells
to CD8 (see 186910)-positive T cells after partial degradation of the
antigens to 8- or 9-amino acid peptides, which is mediated by lysosomal
proteases in an acidic environment. Savina et al. (2006) showed that
DCs, but not macrophages, had an active machinery of phagosomal
alkalinization that maintained the phagosomal pH between 7 and 7.5 for
the first few hours after phagocytosis. Upon inactivation of the
vacuolar ATPase (see 607028), the phagosomal pH in DCs, but not
macrophages, alkalinized strongly. Confocal microscopy demonstrated that
NOX2 assembled on DC phagosomes in a gp91-phox subunit-dependent manner,
and that reactive oxygen species were produced in a more sustained
manner in immature DC phagosomes than in macrophage phagosomes. DCs
obtained from mice lacking Nox2 due to deletion of gp91-phox displayed a
rapid phagosomal acidification and increased antigen degradation,
resulting in inefficient antigen crosspresentation. Savina et al. (2006)
concluded that NOX2, a major player in innate immune responses in
neutrophils, is also involved in adaptive immunity through its activity
in DCs.

Prosser et al. (2011) reported that in heart cells, physiologic stretch
rapidly activates reduced-form NOX2 to produce reactive oxygen species
(ROS) in a process dependent on microtubules (X-ROS signaling). ROS
production occurs in the sarcolemmal and t-tubule membranes where NOX2
is located and sensitizes nearby ryanodine receptors in the sarcoplasmic
reticulum. This triggers a burst of Ca(2+) sparks, the elementary Ca(2+)
release events in heart. Although this stretch-dependent 'tuning' of
ryanodine receptors increases Ca(2+) signaling sensitivity in healthy
cardiomyocytes, in disease it enables Ca(2+) sparks to trigger
arrhythmogenic Ca(2+) waves. In the mouse model of Duchenne muscular
dystrophy (310200), hyperactive X-ROS signaling contributes to
cardiomyopathy through aberrant Ca(2+) release from the sarcoplasmic
reticulum. Prosser et al. (2011) concluded that X-ROS signaling thus
provides a mechanistic explanation for the mechanotransduction of Ca(2+)
release in the heart and offers fresh therapeutic possibilities.

MAPPING

By positional cloning, Royer-Pokora et al. (1986) identified the CYBB
gene at Xp21.

Brockdorff et al. (1988) used the cloned CYBB gene to map the mouse
homolog to the X chromosome in an interspecific Mus domesticus/M.
spretus cross.

MOLECULAR GENETICS

- X-Linked Chronic Granulomatous Disease

In a patient with variant cytochrome b-positive X-linked CGD, Dinauer et
al. (1989) identified a mutation in the CYBB gene (300481.0001). In 6
patients with X-linked CGD, both cytochrome b-negative and cytochrome
b-positive forms, Bolscher et al. (1991) identified 6 different point
mutations in the CYBB gene (300481.0002-300481.0007).

A remarkable family was described by de Boer et al. (1998) in which 2
brothers had CGD due to different mutations in the CYBB gene. One had a
3-kb deletion comprising exon 5 and the other a 3.5-kb deletion
comprising exons 6 and 7. Sequence analysis of PCR-amplified genomic DNA
showed that these deletions overlapped for 35 bp. Analysis by RFLP of
genomic DNA from the mother's leukocytes showed her to be a carrier of
both deletions in addition to the normal CYBB sequence, indicating
triple somatic mosaicism. The presence of a normal CYBB gene in the
mother was also proven by the finding of normal superoxide-generating
neutrophils in addition to cells lacking this ability. Triple X syndrome
was excluded. The finding suggested that the mutations resulted from an
event in early embryogenesis in the mother, possibly involving a
mechanism such as sister chromatid exchange.

Noack et al. (2001) described a second case of somatic triple mosaicism,
the mutation in the patient being the insertion of 12 bp in intron 11,
accompanied by the deletion of exon 12. The grandmother of this patient
was chimeric, carrying a normal allele, the patient's allele, and an
allele with a 4-nucleotide insertion at a site adjacent to the patient's
insertion, in combination with a 1.5-kb deletion within intron 11. The
patient's mother carried a normal allele and the patient's allele. Noack
et al. (2001) proposed that an initial mutational event during the
grandmother's embryogenesis had undergone unsuccessful DNA repair and
resulted in 2 aberrant alleles, 1 of which had been inherited by the
patient and his mother.

Rae et al. (1998) identified the mutations in the CYBB gene responsible
for X-linked CGD in 131 consecutive independent kindreds. Screening by
SSCP analysis identified mutations in 124 of the kindreds, and
sequencing of all exons and intron boundary regions revealed the other 7
mutations. They detected 103 different specific mutations; no single
mutation appeared in more than 7 independent kindreds. The types of
mutations included large and small deletions (11%), frameshifts (24%),
nonsense mutations (23%), missense mutations (23%), splice region
mutations (17%), and regulatory-region mutations (2%). The distribution
of mutations within the CYBB gene exhibited great heterogeneity, with no
apparent mutation hotspots. Evaluation of 87 available mothers revealed
X-linked carrier status in all but 10. The heterogeneity of mutations
and the lack of any predominant genotype indicate that the disease
represents many different mutational events, without a founder effect,
as is expected for a disorder with a previously lethal phenotype.

- X-Linked Familial Atypical Mycobacteriosis-2

In 7 males from 2 kindreds with X-linked familial atypical
mycobacteriosis-2 (AMCBX2; 300645), Bustamante et al. (2011) identified
missense mutations in the CYBB gene (300481.0022 and 300481.0023). All
clinically affected males in both kindreds were hemizygous for the
mutated allele, whereas other maternally related healthy males tested
were not. All 11 obligate female carriers tested in the 2 kindreds were
heterozygous for the mutated allele. Bustamante et al. (2011) found that
all affected males, as well as other family members, had normal NADPH
oxidase activity in circulating neutrophils and monocytes, unlike
individuals with CGD or variant CGD. However, in vitro differentiation
of monocytes to macrophages in the presence of MCSF (CSF1; 120420)
revealed that NADPH oxidase activity was impaired in patient
macrophages, and the ability to control the growth of BCG was reduced.
Impairment of NADPH oxidase activity was also demonstrable in patient
B-cell lines. Immunoblot analysis showed reduced expression of CYBB in
patient neutrophils and monocytes, with a much greater reduction in
monocyte-derived macrophages. Immunohistochemistry showed impaired
production of CYBB in patient lymph node macrophages. Bustamante et al.
(2011) concluded that the CYBB mutations in these 7 adult patients, who
had no history of other granulomatous or infectious diseases, resulted
in dysfunction of macrophages, but not in dysfunction of granulocytes or
monocytes.

ANIMAL MODEL

Enhanced redox stress and inflammation are associated with progression
of amyotrophic lateral sclerosis (ALS; 105400). Marden et al. (2007)
evaluated the effects of Nox1 or Nox2 deletion on transgenic mice
overexpressing human SOD1 (147450) with the ALS-associated gly93-to-ala
mutation (G93A; 147450.0008) by monitoring the onset and progression of
disease using various indices. Disruption of either Nox1 or Nox2
significantly delayed progression of motor neuron disease in these mice.
However, 50% survival rates were enhanced significantly more by Nox2
deletion than Nox1 deletion. Female mice lacking 1 copy of the
X-chromosomal Nox1 or Nox2 genes also exhibited significantly increased
survival rates, suggesting that in the setting of random X-inactivation,
a 50% reduction in Nox1- or Nox2-expressing cells has a substantial
therapeutic benefit in ALS mice. Marden et al. (2007) concluded that
NOX1 and NOX2 contribute to the progression of ALS.

*FIELD* AV
.0001
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT
CYBB, PRO415HIS

In a patient with the variant form of cytochrome b-positive X-linked CGD
(306400), Dinauer et al. (1989) demonstrated a C-A transversion in the
CYBB gene, resulting in a pro415-to-his (P415H) substitution in the
mature protein.

.0002
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT
CYBB, GLY389ALA

In a patient with variant X-linked CGD (306400), in which there is some
residual expression of cytochrome b, Bolscher et al. (1991) identified a
G-to-C transversion in the CYBB gene, resulting in a gly389-to-ala
(G389A) substitution.

.0003
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, HIS209TYR

In a patient with classic CGD (306400), Bolscher et al. (1991)
identified a C-to-T change in the CYBB gene, resulting in a
his209-to-tyr (H209Y) substitution.

.0004
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, ARG73TER

In a patient with classic CGD (306400), Bolscher et al. (1991)
identified a nonsense mutation in the CYBB gene: a C-to-T change
resulting in an arg73-to-ter (R73X) substitution.

.0005
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT
CYBB, CYS244SER

In a patient with variant CGD (306400), Bolscher et al. (1991)
identified a T-to-C transition in the CYBB gene, resulting in a
cys244-to-ser (C244S) substitution.

.0006
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT
CYBB, ALA156THR

In a patient with a variant form of CGD (306400), Bolscher et al. (1991)
identified a G-to-A transition in the CYBB gene, resulting in an
ala156-to-thr (A156T) substitution.

.0007
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT
CYBB, HIS101ARG

In a patient with a classic form of CGD (306400), Bolscher et al. (1991)
identified an A-to-G transition in the CYBB gene, resulting in a
his101-to-arg (H101R) substitution.

.0008
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, EX12DEL

In a patient with X-linked CGD (306400), Schapiro et al. (1991)
identified a 30-nucleotide deletion involving nucleotides 1464-1491
(numbered according to the system of Orkin (1989)) in the CYBB gene. The
encoded polypeptide, normally composed of 570 amino acids, was predicted
to lack residues 488-497. Since the deletion began precisely at the
5-prime end of exon 12 in the gp91-phox gene, mutation in the 3-prime
splice acceptor site was suspected. An A-to-G mutation in the AG 3-prime
acceptor dinucleotide was found. A downstream cryptic acceptor site in
the coding sequence in exon 12 must have been used during mRNA splicing
of the mutant gene. The patient was a 69-year-old white man who had been
in excellent health without antecedent infections until a febrile
illness with a blood culture positive for Pseudomonas cepacia. The
family history was remarkable for a son of the man's daughter who had
died at the age of 5 years from P. cepacia pneumonia complicating
presumptive CGD. The good health of the grandfather may highlight the
importance of oxygen-independent microbicidal pathways and of cytokines
such as interferon gamma (147570) and granulocyte-macrophage
colony-stimulating factor (138960) that can augment phagocyte function
in vivo.

.0009
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, ARG226TER

Curnutte et al. (1992) described a woman with X-linked CGD (306400),
whose neutrophils failed to generate detectable levels of superoxide and
were uniformly nonreactive in the nitroblue tetrazolium test. The
patient was found to be heterozygous for a 688C-T change in the CYBB
gene, resulting in an arg226-to-ter (R226X) nonsense mutation. This
mutation was not present in either the mother or the father. The patient
was also heterozygous for the G6PD polymorphism involving nucleotide
1311T or 1311C (305900.0018). Curnutte et al. (1992) pointed out that
this polymorphism affords a method of determining which X chromosome is
active in a tissue by PCR amplification of cDNA. Since mRNA is made only
from the active X chromosome, this method allows one to determine the
ratio of activities of the X chromosomes in a tissue sample. In
artificial mixtures of amplified cDNA, ratios as low as 1:20 were
detected. Twenty to fifty percent of women of all races are heterozygous
for the nucleotide 1311 polymorphism. Within the limits of the
sensitivity of this method, all of the patient's granulocytes used only
one of her X chromosomes for mRNA production, namely, the one
contributed by the father. Since the mutation was absent from the
father's somatic cells, it presumably represented a new mutation in the
paternal germline.

.0010
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, IVS3, G-A, +5

In a family with chronic granulomatous disease (306400), de Boer et al.
(1992) demonstrated a G-to-A transition at the fifth base of the donor
splice site of intron 3 of the CYBB gene, resulting in the skipping of
exon 3. An expectant mother was diagnosed as a carrier. Analysis of
PCR-amplified genomic DNA from a chorionic villus biopsy showed the same
mutation in the male fetus. The diagnosis was confirmed by conventional
methods after termination of the pregnancy.

.0011
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, ASP500GLY

In a patient with X-linked CGD (306400), Leusen et al. (1994) identified
a 1511A-G transition in exon 15 of the CYBB gene, resulting in an
asp500-to-gly (D500G) substitution. The mutation was associated with
normal amounts of nonfunctional cytochrome b(558) in the patient's
neutrophils. Asp-500 of gp91-phox resides in a region critical for
stable binding of p47-phox and p67-phox.

.0012
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT
CYBB, HIS101TYR

In a patient diagnosed with X-linked chronic granulomatous disease
(306400), Tsuda et al. (1998) reported a C-to-T transition in the CYBB
gene, resulting in a his101-to-tyr (H101Y) substitution. The patient
showed a complete absence of O(2)-forming NADPH oxidase activity, but
immunoblot analysis detected p22-phox and gp91-phox at about 10% of
control amounts. These results provided evidence that histidine-101 of
gp91-phox is one of the heme-binding ligands of cytochrome-b(558).

.0013
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, 250GCG-GCA

Ishibashi et al. (2000) found a splicing mutation in the CYBB gene in 2
brothers with CGD (306400). The last 3 nucleotides of exon 3 in
converted from GCG to GCA, resulting in deletion of exon 3 in some of
the mRNA. The ratio of expression of normally and alternatively spliced
mRNA was found to be different between the proband and his affected
brother. A total of 5 families with the same mutation had been reported
from western countries (Roos et al., 1996; Rae et al., 1998), and from
China (Hui et al., 1996). The case reported by Rae et al. (1998) had
both normal and alternatively spliced mRNA sequences. Another patient
with this same mutation was 37 years old at the time of report and had
been comparatively well; his brother died of septicemia at the age of 9
years and his daughter had been diagnosed as a CGD carrier. On the basis
of the work of Eissa et al. (1996), Ishibashi et al. (2000) raised the
possibility that a cytokine affects the splicing efficiency or
stabilization of mRNA of the CYBB gene.

.0014
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, IN5, L1 INS

Long interspersed nuclear element-1 (LINE-1, or L1 elements; see 151626)
are DNA elements present in the genome in high copy number and are
capable of active retrotransposition. Meischl et al. (2000) stated that
LINE-1 sequences had been implicated in 13 cases of human disease, in
most instances due to insertion into the coding sequences of the
affected genes. They described a patient with CGD (306400) caused by L1
insertion into an intronic sequence of the CYBB gene. Due to internal
rearrangements, the insert in intron 5 introduced new splice sites. This
resulted in a highly heterogeneous splicing pattern with introduction of
2 L1 fragments as new exons into the transcripts and concomitant
skipping of exonic coding sequence. Because no wildtype cDNA was found,
this mechanism was probably responsible for the patient's phenotype. The
L1 fragment, which belonged to the Ta subset of transcriptionally active
LINEs, illustrated a new mechanism by which these elements can modify
the transcribed coding sequence of genes.

.0015
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, 252G-A

Ishibashi et al. (2001) described a Japanese family in which 5 male
cousins in 4 separate sibships, the sons of 4 sisters, had CGD (306400)
and a 252G-A transition at the last nucleotide of exon 3 of the CYBB
gene, changing the last codon from GCG to GCA. Although
transcriptionally silent, the mutation interfered with splicing. Three
of the cousins, aged 13, 17, and 16 years, were treated with 1
subcutaneous dose of interferon-gamma, which resulted in greatly
increased neutrophil superoxide-generating ability and partial
correction of abnormal splicing of the CYBB gene transcripts. Three of
the descendants in this family had died young of severe bacterial
infection, suggesting that they had CGD. The authors noted that an
intractable acne vulgaris of the face in 2 patients disappeared after
treatment with interferon-gamma.

.0016
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT
CYBB, HIS303ASN

Stasia et al. (2002) described 2 atypical cases of X-linked CGD (306400)
in male first cousins in whom cytochrome b(558) was present at a normal
level, but was not functional. The boys were 16 years old at the time of
the study. One boy presented at the age of 9 months with a reaction due
to Calmette-Guerin bacillus (BCG) with associated axillary
lymphadenitis. At the age of 8 years, he developed a liver abscess
caused by S. aureus and CGD was diagnosed by the absence of NBT
reduction in neutrophils. The NBT slide test gave normal results in the
father and intermediate values in the mother, both of whom were in good
health. The maternal first cousin presented with a similar clinical
history, and CGD was diagnosed at the age of 8 years. Stasia et al.
(2002) identified 2 base substitutions in the CYBB gene, 919C-A and
923C-G, resulting in his303-to-asn (H303N) and pro304-to-arg (P304R;
300481.0017) changes in the C-terminal tail of the protein. The mothers
of the cousins had both wildtype and mutated alleles. FAD was present in
normal amounts in neutrophil membranes, both in the patients and their
parents. The mutated gp91-phox still functioned as a proton channel;
however, association of the cytosolic factors p47-phox and p67-phox with
the membrane fraction was strongly disrupted. Stasia et al. (2002)
concluded that residues 303 and 304 are crucial for the stable assembly
of the NADPH oxidase complex and for electron transfer, but not for its
proton channel activity.

In stably transfected PLB-985 cells, Bionda et al. (2004) demonstrated
that the H303N mutation completely inhibited NADPH oxidase activity,
whereas the P304R mutation reduced it to 4% of wildtype activity. NADPH
oxidase assembly was abolished in H303N mutant cells, but the
translocation was only attenuated in P304R mutants. Bionda et al. (2004)
concluded that neither mutation is a polymorphism.

.0017
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, PRO304ARG

See 300481.0016, Stasia et al. (2002), and Bionda et al. (2004).

.0018
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, IVS5, G-T, +978

In a 9-month-old boy with chronic granulomatous disease (306400)
manifested by neutrophils that failed to reduce NBT and a history of
otitis media, Noack et al. (2001) identified an unusual intronic
mutation in the CYBB gene: a 978G-T transversion in intron 5 that
created a novel 5-prime splice site and resulted in multiple abnormal
mRNA products. His mother had a lifelong history of chronic skin
abscesses and was originally diagnosed as having autosomal recessive CGD
(233690) as a child. As an adult, she was found to have 15% positive
cells in the NBT test and 10% positive by dihydrorhodamine flow
cytometry, suggestive of a carrier of X-linked CGD with skewed X
inactivation.

.0019
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, EX4, L1 INS

In a Dutch male patient with chronic granulomatous disease (306400),
Brouha et al. (2002) identified an insertion of an L1 retrotransposable
element from the site of the precursor L1 locus on 2q24.1, which they
called LRE3, into exon 4 of the CYBB gene. They used a unique
polymorphic C-prime transduction to show that the L1 retrotransposition
event most likely occurred in the maternal primary oocyte during meiosis
I. More than half of recent human L1 insertions have occurred in only 3
genes: CYBB, factor VIII (300841), and dystrophin (DMD; 300377)
(Ostertag and Kazazian, 2001). Brouha et al. (2002) stated that it was
undetermined whether these 3 genes are L1 hotspots or whether this
seeming cluster of L1 activity is the result of an ascertainment bias.

.0020
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED
CYBB, IVS1, T-C, +6

In a patient with X-linked CGD (306400) first reported by Ezekowitz et
al. (1988), Rae et al. (1998) identified a T-to-C change in the 5-prime
splice site of intron 1 of the CYBB gene, resulting in a diminished
level of p91-phox. In this patient, Ezekowitz et al. (1988) found that
interferon-gamma (IFNG; 147570), an activator of phagocytes, resulted in
a 5- to 10-fold increase in superoxide production by granulocytes and
monocytes, a proportionate rise in granulocyte bactericidal activity,
and an increase in the cellular contents of phagocyte cytochrome b and
immunoreactive cytochrome b heavy chain. In other CGD group studies,
however, no apparent increases in phagocyte superoxide generation were
observed. For that reason, the patient studied by Ezekowitz et al.
(1988) was considered to be an exceptional case. Condino-Neto and
Newburger (2000) proposed that IFN-gamma improved the splicing
efficiency of CYBB gene transcripts in that patient and corrected a
nuclear processing defect due to the intronic mutation by augmenting
nuclear export of normal transcripts.

.0021
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, SOMATIC MOSAIC
CYBB, 90CCG-GGT

In an 80-year-old woman of Iraqi origin with CGD (306400), Wolach et al.
(2005) identified a novel somatic mutation in the CYBB gene in
heterozygous form: in the sequence 88-93TACCGG, nucleotides CCG were
changed to GGT, resulting in tyr30-to-ter (Y30X) and arg31-to-val (R31V)
substitutions. In the patient's leukocytes, the nonmutated CYBB allele
had apparently been inactivated. Only 0.4 to 2% of her neutrophils
showed NADPH oxidase activity. This extreme skewing of X-chromosome
inactivation was not found in cheek mucosal cells where the CYBB
mutation was not present. The mutation was barely detectable in the DNA
from memory T lymphocytes. Wolach et al. (2005) concluded that this
patient showed somatic mosaicism for the CYBB mutation, which probably
originated during her lifetime in her bone marrow. The patient had had a
normal and healthy life until age 66. Thereafter, she underwent about 30
hospitalizations within 8 years, for Serratia marcescens sepsis,
recurrent pneumonia (5 times) and sinusitis (2 times), Staphylococcal
aureus pretibial abscess, Acinetobacter skin abscess, Escherichia coli
and Candida albicans urinary tract infections, Providentia osteomyelitis
and septic arthritis, suppurative adenitis, liver cysts and calcified
lesions, panuveitis, anthralgia, vaginal ulcers, aphthous stomatitis,
pyoderma gangrenosum, and vasculitis-like skin rash on face and limbs.
After the diagnosis of chronic granulomatous disease was established at
the age of 74 years, she was successfully treated with
trimethoprim-sulfamethoxazole on a prophylactic daily basis, and no more
hospitalizations or relevant infections occurred.

.0022
ATYPICAL MYCOBACTERIOSIS, FAMILIAL, X-LINKED 2
CYBB, GLU231PRO

In 4 maternally related French males with X-linked familial atypical
mycobacteriosis-2 (AMCBX2; 300645) previously reported by Bustamante et
al. (2007), Bustamante et al. (2011) identified an A-to-C transversion
in exon 7 of the CYBB gene that resulted in a glu231-to-pro (Q231P)
substitution in the third extracellular loop of the protein. The
mutation resulted in an impaired respiratory burst in macrophages, but
not in granulocytes or monocytes. Three of the patients had BCG disease,
and 1, who had not been vaccinated with BCG, had tuberculosis. The
patients were otherwise healthy, with no clinical chronic granulomatous
disease (CGD; 306400), a finding confirmed by laboratory tests.

.0023
ATYPICAL MYCOBACTERIOSIS, FAMILIAL, X-LINKED 2
CYBB, THR178PRO

In 3 maternally related French males with X-linked familial atypical
mycobacteriosis-2 (AMCBX2; 300645), Bustamante et al. (2011) identified
an A-to-C transversion in exon 6 of the CYBB gene that resulted in a
thr178-to-pro (T178P) substitution in the transmembrane region of the
protein. The mutation resulted in an impaired respiratory burst in
macrophages, but not in granulocytes or monocytes. All 3 patients had
BCG disease. They were otherwise healthy, with no clinical chronic
granulomatous disease (CGD; 306400), a finding confirmed by laboratory
tests.

*FIELD* SA
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Orkin (1988); Dinauer et al. (1987)
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(X91+) case with a double missense mutation in the cytosolic gp91phox
C-terminal tail. Biochim. Biophys. Acta 1586: 316-330, 2002.

39. Teahan, C.; Rowe, P.; Parker, P.; Totty, N.; Segal, A. W.: The
X-linked chronic granulomatous disease gene codes for the beta-chain
of cytochrome b(-245). Nature 327: 720-721, 1987.

40. Tsuda, M.; Kaneda, M.; Sakiyama, T.; Inana, I.; Owada, M.; Kiryu,
C.; Shiraishi, T.; Kakinuma, K.: A novel mutation at a probable heme-binding
ligand in neutrophil cytochrome b(558) in atypical X-linked chronic
granulomatous disease. Hum. Genet. 103: 377-381, 1998.

41. Wolach, B.; Scharf, Y.; Gavrieli, R.; de Boer, M.; Roos, D.:
Unusual last presentation of X-linked chronic granulomatous disease
in an adult female with a somatic mosaic for a novel mutation in CYBB. Blood 105:
61-66, 2005.

*FIELD* CN
Ada Hamosh - updated: 11/22/2011
Paul J. Converse - updated: 6/14/2011
Patricia A. Hartz - updated: 3/3/2008
Paul J. Converse - updated: 2/20/2007
Paul J. Converse - updated: 10/27/2005
Marla J. F. O'Neill - updated: 4/25/2005
Victor A. McKusick - updated: 3/21/2005

*FIELD* CD
Cassandra L. Kniffin: 3/2/2004

*FIELD* ED
terry: 11/13/2012
alopez: 11/29/2011
terry: 11/22/2011
mgross: 8/18/2011
terry: 6/14/2011
carol: 4/7/2011
terry: 11/25/2009
mgross: 3/3/2008
mgross: 2/21/2007
mgross: 2/20/2007
mgross: 11/7/2005
terry: 10/27/2005
terry: 8/3/2005
wwang: 4/29/2005
wwang: 4/27/2005
terry: 4/25/2005
carol: 3/30/2005
wwang: 3/24/2005
terry: 3/21/2005
carol: 3/15/2004
ckniffin: 3/15/2004
carol: 3/12/2004
terry: 3/12/2004
ckniffin: 3/11/2004

MIM 300645
*RECORD*
*FIELD* NO
300645
*FIELD* TI
#300645 ATYPICAL MYCOBACTERIOSIS, FAMILIAL, X-LINKED 2; AMCBX2
;;ATYPICAL MYCOBACTERIAL INFECTION, DISSEMINATED, X-LINKED 2;;
read moreATYPICAL MYCOBACTERIAL INFECTION, FAMILIAL DISSEMINATED, X-LINKED
2;;
MYCOBACTERIAL DISEASE, SUSCEPTIBILITY TO, X-LINKED 2;;
MYCOBACTERIAL DISEASE, MENDELIAN SUSCEPTIBILITY TO, X-LINKED RECESSIVE
2; XRMSMD2
*FIELD* TX
A number sign (#) is used with this entry because X-linked familial
atypical mycobacteriosis-2 is caused by mutations in the CYBB gene
(300481).

For a general phenotypic description and a discussion of genetic
heterogeneity of familial atypical mycobacteriosis, see 209950.

For information on X-linked familial atypical mycobacteriosis-1, which
is caused by mutations in the NEMO gene (300248), see 300636.

CLINICAL FEATURES

Bustamante et al. (2007) studied a large French kindred in which 4 male
maternal relatives had recurrent mycobacterial disease, suggesting
X-linked recessive inheritance. Three patients had recurrent disease
caused by BCG, and 1 had recurrent tuberculosis. The infections showed
tropism for lymph nodes, in which granulomas exhibiting caseous
necrosis, but no acid-fast bacilli, were observed. The patients, aged 32
to 55 years at the time of report, all responded to antibiotic therapy
and/or surgical excision. A common childless maternal aunt had been
successfully treated for pulmonary tuberculosis that also involved the
reproductive system. The mother of 2 patients had a history of
asymptomatic, untreated latent tuberculosis.

Bustamante et al. (2011) identified a second kindred consisting of 3
French maternally related males, aged 36 to 41 years at the time of
report, with mendelian susceptibility to mycobacterial disease (MSMD)
manifesting as BCG disease after neonatal vaccination. Patients from
this kindred and the one previously reported by Bustamante et al. (2007)
displayed no distinguishable immunologic phenotype.

MAPPING

By immunologic, biochemical, genetic, and linkage analyses, Bustamante
et al. (2007) excluded mutations in 5 autosomal genes and the X-linked
NEMO gene as the cause of recurrent mycobacterial disease in 4 male
patients from a large French kindred. Linkage analysis of the X
chromosome implicated 2 candidate regions, Xp21.2-p11.4, which contains
129 genes, and Xq25-q26.3, which contains 70 genes, with a maximum lod
score of 2.

MOLECULAR GENETICS

In the kindred they reported with X-linked MSMD, Bustamante et al.
(2011) identified a thr178-to-pro (T178P; 300481.0023) mutation in the
CYBB gene. In the kindred reported by Bustamante et al. (2007),
Bustamante et al. (2011) identified a glu231-to-pro (Q231P; 300481.0022)
mutation in the CYBB gene. All clinically affected males in both
kindreds were hemizygous for the mutated allele, whereas other
maternally related healthy males tested were not. All 11 obligate female
carriers tested in the 2 kindreds were heterozygous for the mutated
allele. Male founders of both kindreds did not develop mycobacterial
disease, but they lived in France before the introduction of routine BCG
vaccination. CYBB mutations are commonly associated with chronic
granulomatous disease (CGD; 306400), but Bustamante et al. (2011) found
that all affected males, as well as other family members, had normal
NADPH oxidase activity in circulating neutrophils and monocytes, unlike
individuals with CGD or variant CGD. However, in vitro differentiation
of monocytes to macrophages in the presence of MCSF (CSF1; 120420)
revealed that NADPH oxidase activity was impaired in patient
macrophages, and the ability to control the growth of BCG was reduced.
Impairment of NADPH oxidase activity was also demonstrable in patient
B-cell lines. Immunoblot analysis showed reduced expression of CYBB in
patient neutrophils and monocytes, with a much greater reduction in
monocyte-derived macrophages. Immunohistochemistry showed impaired
production of CYBB in patient lymph node macrophages. Bustamante et al.
(2011) concluded that the CYBB mutations in these 7 adult patients with
MSMD (including 1 patient with tuberculosis), who had no history of
other granulomatous or infectious diseases, resulted in dysfunction of
macrophages, but not in dysfunction of granulocytes or monocytes.

*FIELD* RF
1. Bustamante, J.; Arias, A. A.; Vogt, G.; Picard, C.; Galicia, L.
B.; Prando, C.; Grant, A. V.; Marchal, C. C.; Hubeau, M.; Chapgier,
A.; de Beaucoudrey, L.; Puel, A.; and 18 others: Germline CYBB
mutations that selectively affect macrophages in kindreds with X-linked
predisposition to tuberculosis mycobacterial disease. Nature Immunol. 12:
213-221, 2011.

2. Bustamante, J.; Picard, C.; Fieschi, C.; Filipe-Santos, O.; Feinberg,
J.; Perronne, C.; Chapgier, A.; de Beaucoudrey, L.; Vogt, G.; Sanlaville,
D.; Lemainque, A.; Emile, J.-F.; Abel, L.; Casanova, J.-L.: A novel
X-linked recessive form of Mendelian susceptibility to mycobacterial
disease. J. Med. Genet. 44: e65, 2007. Note: Electronic Article.

*FIELD* CS
INHERITANCE:
X-linked recessive

IMMUNOLOGY:
Recurrent mycobacterial disease (BCG and M. tuberculosis);
Varicella zoster infection

*FIELD* CD
Kelly A. Przylepa: 10/15/2008

*FIELD* ED
joanna: 10/15/2008

*FIELD* CN
Paul J. Converse - updated: 6/14/2011

*FIELD* CD
Paul J. Converse: 3/22/2007

*FIELD* ED
mgross: 08/18/2011
terry: 6/14/2011
mgross: 3/26/2007
mgross: 3/22/2007

MIM 306400
*RECORD*
*FIELD* NO
306400
*FIELD* TI
#306400 GRANULOMATOUS DISEASE, CHRONIC, X-LINKED; CGD
;;CYTOCHROME b-NEGATIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED;;
read moreCHRONIC GRANULOMATOUS DISEASE, X-LINKED
CYTOCHROME b-POSITIVE GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, INCLUDED;;
GRANULOMATOUS DISEASE, CHRONIC, X-LINKED, VARIANT, INCLUDED;;
CHRONIC GRANULOMATOUS DISEASE, ATYPICAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because X-linked chronic
granulomatous disease (CGD) is caused by mutation in the gene encoding
p91-phox (CYBB; 300481).

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 phagocyte NADPH oxidase (phox)
complex, which generates the microbicidal 'respiratory burst' (reviewed
by Dinauer et al., 2001 and Johnston, 2001).

- Genetic Heterogeneity of Chronic Granulomatous Disease

Chronic granulomatous disease can be caused by mutations in any 1 of 5
genes encoding structural or regulatory subunits of the phagocyte NADPH
oxidase complex. See also autosomal recessive cytochrome b-negative CGD
(233690), caused by mutation in the CYBA gene (608508); autosomal
recessive cytochrome b-positive CGD type I (233700), caused by mutation
in the NCF1 gene (608512); autosomal recessive cytochrome b-positive CGD
II (608515), caused by mutation in the NCF2 gene (608515); and autosomal
recessive cytochrome b-positive CGD type III (613960), caused by
mutation in the NCF4 gene (601488).

A similar syndrome, termed neutrophil immunodeficiency syndrome
(608203), is caused by mutation in another protein involved in the NADPH
oxidase complex, RAC2 (602049).

CLINICAL FEATURES

Dinauer et al. (2001) suggested that Janeway et al. (1954) first noted
CGD in a patient with hypergammaglobulinemia associated with severe
recurrent and chronic nonspecific infections, but did not distinguish
the disorder as a distinct entity. Berendes et al. (1957) and Bridges et
al. (1959) identified a new syndrome which they termed 'fatal
granulomatosis of childhood.' Four boys had suppurative lymphadenitis,
hepatosplenomegaly, pulmonary infiltrates, and eczematoid dermatitis,
with findings of granulomas in biopsy and autopsy specimens. Landing and
Shirkey (1957) described 2 boys with recurrent infection who had
infiltration of visceral organs by pigmented lipid histiocytes. Carson
et al. (1965) reported 16 males in 8 families with a syndrome of chronic
suppurative lymphadenitis, chronic dermatitis, chronic pulmonary disease
and hepatosplenomegaly with subsequent fatal outcome.
Hypergammaglobulinemia was often present. Quie et al. (1967) observed a
form of fatal granulomatous disease in males in an X-linked pedigree
pattern. The leukocytes were able to phagocytize staphylococci normally,
but were defective in their ability to digest the organism.

In a series of 6 males with CGD, aged 2 to 22 years, Lischner and Martyn
(1975) described chorioretinal lesions, sea-blue histiocytes, and
changes misconstrued as indicative of eosinophilic granuloma. Dilworth
and Mandell (1977) reported 4 adult male sibs, aged 28, 30, 32, and 40,
who had the onset at age 6 years of serious bacterial infections
involving the lungs and lymph nodes followed by a marked decrease in the
frequency of infections in their mid-twenties. Sequelae included
pulmonary fibrosis, ill-defined polyarthritis and glomerulonephritis.
Despite normal morphology and the ability to ingest microbes,
postphagocytic polymorphonuclear leukocytes failed to reduce nitroblue
tetrazolium (NBT), consume oxygen and produce hydrogen peroxide, and
stimulate the hexose monophosphate shunt. G6PD (305900) levels were
normal. An intermediate quantitative NBT in the mother of the brothers
and in a daughter of each of 2 of them supported X-linked recessive
inheritance.

Bohler et al. (1986) studied 25 patients with CGD. In 18 of 22
clinically typical cases, the complete inability of superoxide
generation by granulocytes was associated with the absence of detectable
cytochrome b. Mothers, but not fathers, of such male patients showed
diminished content of cytochrome b, confirming that the affected gene is
localized on the X chromosome. Flavoprotein deficiency found in the
granulocytes of 4 male patients was always associated with absence of
detectable cytochrome b. Three further patients had a mild form of
X-linked CGD; the oxidative activity of their phagocytes and the
cytochrome b were diminished but not absent. Southwick and van der Meer
(1988) described recurrent episodes of severe cystitis in 2 unrelated
men, aged 23 and 20 years, with X-linked CGD. Ultrasonography showed
large, discrete bladder masses that mimicked bladder carcinoma in both
patients. Prolonged antibiotic therapy was necessary for clearing of the
inflammatory bladder masses.

Johnston (2001) reviewed the clinical aspects of CGD. The disorder
presents most often with pneumonia, infectious dermatitis,
osteomyelitis, and recurrent or severe abscess formation beneath the
skin and in the organs of the mononuclear phagocyte system. Tissue
examination typically shows microscopic granulomas. The estimated
incidence of CGD in the U.S. is 1/200,000 births per year. Of 368
patients with CGD, approximately 76% had the X-linked recessive form,
18% had disease due to p47-phox (608512) deficiency, 4% due to p67-phox
(233710) deficiency, and 3% due to p22-phox (608508) deficiency.
Johnston (2001) found that the organisms infecting CGD patients in the
1990's changed markedly from those reported from 1957 to 1976.
Initially, Staphylococcus, Klebsiella, and E. coli were the most common
organisms, whereas Aspergillus nidulans, Candida, Burkholderia cepacia
(formerly Pseudomonas cepacia), and Serratia marcescens had become more
prominent since then. Secondary complications in patients with CGD
include enteritis/colitis, obstruction of the urinary tract, discoid
lupus, and chorioretinitis.

- Variant or Atypical CGD

Lew et al. (1981) described a man with what the authors termed a
'variant' form of CGD. The disorder resembled CGD in some respects, but
differed by showing normal activation of phagocyte membrane oxidase.
However, the oxidase showed reduced activity under physiologic
conditions because of an apparent altered affinity for reduced NADP.
Granulocytes from the patient's mother, but not those of the father,
exhibited defective superoxide production, supporting X-linked
inheritance. The proband had only mild infections limited to the skin
and no history of the usual systemic or visceral infections. At age 16,
he developed thrombocytopenia which responded to steroids, and, at age
19, splenectomy. The mother had discoid lupus erythematosus, a disease
reported to be associated with the CGD carrier state (Schaller, 1972).
The maternal grandfather had a lifelong history of skin infections and
was said to have died of tuberculosis at age 62.

In general, X-linked CGD is cytochrome b-negative. However, Borregaard
et al. (1983) reported a family with X-linked, cytochrome b-positive
CGD. Curnutte (1988) suggested the existence of a fourth type of CGD,
CGD type IV, which is exceedingly rare and is characterized by X-linked
inheritance but normal levels of cytochrome b. He reported 2 brothers
with this disorder, referred to 4 other cases with a similar clinical
picture, and suggested that these cases are allelic variants.

Clark et al. (1989) concluded that the X-linked cytochrome b-negative
type of CGD due to deficiency of the beta subunit of cytochrome b
represents about 51% of cases of CGD. Another 5% of cases of CGD have an
X-linked cytochrome b-positive form, which is allelic to the X-linked
cytochrome b-negative form, in which a mutation preserves a functionally
defective but detectable cytochrome (see 300481.0001 and Dinauer et al.,
1989). Patients with this rare cytochrome b-positive X-linked form of
CGD were reported by Ament and Ochs (1973) and Okamura et al. (1988).

Bolscher et al. (1991) classified CGD cases as 'classic' if there was no
respiratory burst activity demonstrable in a patient's neutrophils and
cytochrome b(558) was absent as determined by absorption spectroscopy;
they classified cases as 'variant' when a patient's neutrophils had
residual burst activity and residual amounts of cytochrome b(558). These
patients may also be referred to as having cytochrome b-positive
X-linked CGD.

- Female Carriers

The mother of the affected boy described by MacFarlane et al. (1967) had
a chronic dermatitis of the neck (Jessner benign lymphocytic
infiltration) and a partial defect in phagocytosis demonstrable in vitro
that was qualitatively identical to that in her son.

Thompson and Soothill (1970) and Kragballe et al. (1981) described an
increased incidence of cutaneous lupus erythematosus (discoid lupus
erythematosus) and recurrent mouth ulcers in female carriers of X-linked
CGD. The degree in reduction of superoxide production was closely
related to the manifestations of clinical disease.

Finlay et al. (1983) suggested that a persistent eruption in
light-exposed areas is a manifestation of the CGD heterozygous state.
They observed the changes in the mother and sister of an affected boy.
Similarities to cutaneous SLE and to Jessner benign lymphocytic
infiltration were noted in earlier reports that have emphasized the
significance of this finding (Brandrup et al., 1981; Nelson et al.,
1977; Schaller, 1972). Finlay et al. (1983) called this CGDCGD (carrier
genodermatosis of chronic granulomatous disease) and suggested that the
skin disorder can be a useful guide in genetic counseling and prenatal
diagnosis.

INHERITANCE

Windhorst et al. (1967) did family studies establishing X-linked
recessive inheritance of CGD, and demonstrating 2 populations of
leukocytes in heterozygous females. Controversy over whether the
inheritance is X-linked or autosomal was illustrated by the letter of
Windhorst (1969) and accompanying reply.

DIAGNOSIS

- Prenatal Diagnosis

Matthay et al. (1984) described a luminol enhanced chemiluminescence
micromethod used for prenatal diagnosis of CGD. Fetal blood was useful,
whereas amniocytes were not.

De Boer et al. (1992) reported successful prenatal diagnosis of CGD
using PCR.

PATHOGENESIS

During phagocytosis, neutrophils undergo the 'respiratory burst,' an
oxidative response in which highly reactive bactericidal oxidative
metabolites, including superoxide, hydrogen peroxide, hydroxyl radicals,
and perhaps singlet oxygen, are formed within the intact phagocyte. The
NADPH oxidase complex is responsible for the respiratory burst. Segal
(1985) gave a useful review of the molecular basis of CGD, viewed as a
syndrome caused by any defect in the function of the electron transport
chain essential to the microbicidal activity of white cells.

In patients with CGD, Baehner and Nathan (1967) demonstrated a defect in
a leukocyte oxidase; the intact leukocytes failed to reduce the redox
dye nitroblue tetrazolium or to show increased oxygen consumption during
phagocytosis. Baehner and Karnovsky (1968) found deficiency of reduced
nicotinamide-adenine dinucleotide oxidase of polymorphonuclear
leukocytes in 5 patients with CGD. In cells from patients with CGD, Quie
et al. (1967) found diminished activity of the bacterial capacity of
polymorphonuclear leukocytes.

In 2 patients with CGD, Curnutte et al. (1974) found low levels of
superoxide production; both patients were male (Babior, 1974). In
granulocyte samples from 3 patients with X-linked CGD, Curnutte et al.
(1975) found that the cells produced no detectable superoxide. The
failure was not due to an inhibitor. Samples from the mothers of 2 of
the patients produced superoxide at diminished rate, whereas samples
from the third mother had normal superoxide production. Hohn and Lehrer
(1974) found deficiency of NADPH oxidase as the presumed basic defect in
X-linked CGD. In neutrophils from a patient with CGD, Segal and Peters
(1976) demonstrated a defect in an NADH-dependent enzyme located in the
plasma membrane that reduces NBT. McPhail et al. (1977) also presented
evidence that NADPH oxidase activity is deficient in CGD and suggested
that a failure of activation of the enzyme underlies the deficiency. Of
the 9 patients studied, 7 were considered to have the autosomal
recessive and 2 the X-linked type. No physiologic difference between the
types was detected.

In neutrophils of patients with CGD, Segal et al. (1978) demonstrated
absence of a newly described heme-containing cytochrome b(-245).
Obligatory CGD heterozygotes showed intermediate levels of the
cytochrome b. The authors noted that the burst of oxygen metabolism
associated with phagocytosis is not to provide energy for the cells, but
rather is involved in the bacterial killing process. Due to the defect
in the oxygen-dependent microbicidal system in CGD, neutrophils are
unable to kill certain bacteria, particularly those that contain
catalase and can catabolize hydrogen peroxide. The cytochrome b
deficient in CGD is independent of cytochrome P450 of the endoplasmic
reticulum and of mitochondrial cytochrome oxidase. Segal et al. (1983)
found that cytochrome b(-245) was undetectable in 19 males with presumed
X-linked CGD; heterozygous female relatives had reduced concentrations
of the cytochrome and variable proportions of cells that were unable to
generate superoxide, these 2 characteristics being closely correlated.
Of the 19 cases, 3 were sporadic with no carrier females in the family.
In all 8 patients, including 7 women, with a probable autosomal
recessive form of CGD, the cytochrome was present but nonfunctional.
Segal et al. (1983) reported an Asian family with affected females with
depressed levels and function of cytochrome b(-245).

Segal (1987) determined that cytochrome b is composed of 2 closely
linked subunits with approximate molecular masses of 23 kD and 91 kD. In
5 patients with X-linked CGD, neither protein was detected. Parkos et
al. (1989) found that neither cytochrome b subunit, p22-phox or
p91-phox, 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.

In an editorial, Karnovsky (1983) noted that genetic defects in CGD may
occur at many levels, since it is an enzyme system rather than a single
enzyme involved in the transmission of electrons during the respiratory
burst. Potential affected steps include stimulation of the cell
membrane; apposition of membrane-bound components of the machinery of
the respiratory burst; the cytoskeleton which may control movement of
membrane or cytoplasmic components; one or more enzymes that reduced
cytochrome b(-245); the amount of the cytochrome present; the intimate
nature of the cytochrome itself.

Variant forms of CGD, both X-linked and autosomal, have been described
in which the patients' phagocytes respond to some but not to all stimuli
of the oxidase system (Tauber et al., 1983). Defects in the activation
system may lead to CGD, as well as absence or defect in a component of
the complex oxidase system that generates superoxide and hydrogen
peroxide. When monocytes from the X-linked and autosomal forms of CGD
were fused, Hamers et al. (1984) showed that the hybrid cells were
cytochrome-b-positive and expressed NBT-reductase activity in the
presence of phorbol myristate acetate (PMA).

Buescher et al. (1985) used the ability or lack of ability to reduce NBT
dye to identify 2 populations of white cells in females heterozygous for
CGD. The findings in 11 heterozygotes were consistent with lyonization
at a stage when 8 embryonic founder cells for the hematopoietic system
were present. Individuals showed little variation, most of it
attributable to experimental error among serial determinations. The
variation remaining after accounting for experimental error suggests the
existence of more than 400 pluripotent stem cells supporting
hematopoiesis. Similar studies have been done using G6PD.

MAPPING

Francke et al. (1985) studied a male patient with 3 X-linked disorders:
chronic granulomatous disease with cytochrome b(-245) deficiency and
McLeod red cell phenotype (300842), Duchenne muscular dystrophy
(310200), and retinitis pigmentosa (see RP3, 300029). A subtle
interstitial deletion of part of Xp21 was demonstrated as the presumed
basis of this 'contiguous gene syndrome.' The close clustering of CGD,
DMD and RP suggested by these findings was inconsistent with separate
linkage data (see HISTORY and Densen et al., 1981), which indicated that
McLeod and CGD are close to Xg and that DMD and RP are far from Xg.
Francke et al. (1985) suggested that the deletion may contain a single
defect affecting perhaps a cell membrane component which underlies all 3
disorders. Using a method for cloning the specific DNA fragment absent
in patients homozygous or hemizygous for chromosomal deletions, Kunkel
et al. (1985) confirmed a minute interstitial deletion of Xp21 in the
patient reported by Francke et al. (1985); see 300679.

Using cloned, polymorphic DNA probes, Baehner et al. (1986) mapped CGD
to Xp21.2-p21.1, proximal to DMD. CGD lies in a region of Xp that
appears to have more recombination than anticipated on the basis of
physical distance between markers. This linkage assignment is
inconsistent with the linkage to Xg, but entirely consistent with the
findings in the boy reported by Francke et al. (1985) with an
interstitial deletion of Xp21, The earlier data on linkage to Xg were
apparently in error.

CLINICAL MANAGEMENT

Ezekowitz et al. (1988) attempted a therapeutic trial using
interferon-gamma (IFNG; 147570), an activator of phagocytes, in CGD.
They observed a 5- to 10-fold increase in superoxide production by
granulocytes and monocytes, a proportionate rise in granulocyte
bactericidal activity, and an increase in the cellular contents of
phagocyte cytochrome b and immunoreactive cytochrome b heavy chain. The
findings of Ezekowitz et al. (1988) motivated multicenter groups to
perform double-blinded clinical studies of IFN-gamma as a prophylactic
agent in CGD, which demonstrated its clinical benefit in most patients.
In these group studies, however, no apparent increases in phagocyte
superoxide generation were observed. For that reason, the patient
studied by Ezekowitz et al. (1988) was considered to be an exceptional
case. Rae et al. (1998) showed that the patient of Ezekowitz et al.
(1988) had a single-base substitution in the sixth position of the first
intron of the CYBB gene (300481.0020). Condino-Neto and Newburger (2000)
proposed that IFN-gamma improved the splicing efficiency of CYBB gene
transcripts in that patient and corrected a nuclear processing defect
due to the intronic mutation by augmenting nuclear export of normal
transcripts.

Ishibashi et al. (2001) demonstrated an IFN-gamma-dependent increase of
superoxide production associated with a change in the mRNA splicing
pattern of CYBB gene transcripts in neutrophils from 3 patients in 1
family who had a silent mutation adjacent to intron 3 of the CYBB gene
(300481.0015). They found significant differences in the splicing
pattern of CYBB gene transcripts in patient neutrophils between days 1
and 25 after administration of IFN-gamma. Furthermore, a complete
transcript containing the missing exons was detected in all specimens
after the treatment. The changes in the splicing pattern of the
transcripts and the prolonged effect on superoxide-generating ability of
the patients' neutrophils indicated that IFN-gamma induced a partial
correction of the abnormal splicing of CYBB gene transcripts in myeloid
progenitor cells.

Ho et al. (1996) reported successful bone marrow transplantation (BMT)
in a 16-month-old Australian Aboriginal boy. His HLA-identical brother
was the donor. The authors reviewed 5 previous reports on BMT in
patients with X-linked CGD.

Horwitz et al. (2001) treated 10 male patients with CGD by
transplantation of peripheral blood stem cells from an HLA-identical sib
after undergoing a nonmyeloablative conditioning regimen consisting of
cyclophosphamide, fludarabine, and antithymocyte globulin. The allograft
was depleted of T cells to reduce the risk of severe graft-versus-host
disease (GVHD; see 614395). To reduce the risk of graft rejection, donor
lymphocytes were infused at intervals after transplantation, according
to a predetermined regimen. After a median follow-up of 17 months, the
proportion of donor neutrophils in the circulation in 8 of 10 patients
was 33 to 100%, a level that could be expected to provide normal host
defense; in 6 patients the proportion was 100%. In 2 patients, graft
rejection occurred. Preexisting granulomatous lesions resolved in the
patients in whom transplantation was successful. Eight of the patients
had the p91-phox founder disease; 1 patient each had the p22-phox form
and the p47-phox form.

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.

In a placebo-controlled study, Gallin et al. (2003) found that
itraconazole is an effective and well-tolerated prophylaxis for fungal
infections in chronic granulomatous disease. Lagakos (2003) commented on
the fact that the trial required 10 years to enroll just 39 patients,
thus illustrating some of the problems and options that arise in the
design of clinical trials for new therapies for rare diseases.

- Gene Therapy

Porter et al. (1993) used retrovirus-mediated expression of gp91-phox to
reconstitute functionally NADPH oxidase activity in B-cell lines from 3
unrelated patients with X-linked CGD. The protein was glycosylated and
membrane-associated, and the reconstituted oxidase was appropriately
activated via protein kinase C. The kinetics of superoxide production by
such reconstituted cells was similar to that of normal B-cell lines.

Ezekowitz (2001) raised the possibility that the ability to purify and
manipulate stem cells from bone marrow (Orkin, 2000) may provide new
approaches to somatic gene therapy. The possibility that single-gene
defects could be repaired in autologous stem cells ex vivo and, on
return to the patient, home selectively to the organ of choice seemed
within reach.

Ott et al. (2006) reported successful treatment of X-linked CGD in 2
unrelated patients with myelosuppression followed by gene therapy using
a monocistronic gammaretroviral vector expressing the p91-phox gene to
transform peripheral blood cells. Gene-modified cells predominantly in
the myeloid fraction were detected as early as 21 days post-reinfusion
and persisted over a year later accompanied by clinical improvement in
both patients. Analysis of retroviral integration sites showed
clustering of activating insertions in or near the PR domain-containing
zinc finger genes MDS1 (600049)-EVI1 (165215) or PRDM16 (605557), or the
SETBP1 gene that influenced regulation of long-term hematopoiesis by
expanding gene-corrected myelopoiesis 3- to 4-fold in both individuals.

MOLECULAR GENETICS

In a patient with cytochrome b-positive X-linked CGD, Dinauer et al.
(1989) identified a mutation in the gene encoding the cytochrome b heavy
chain (CYBB; 300481.0001). In 6 patients with X-linked CGD, both
cytochrome b-negative and cytochrome b-positive forms, Bolscher et al.
(1991) identified 6 different point mutations in the CYBB gene
(300481.0002-300481.0007).

Roos (1994) reviewed all 4 genetic forms of chronic granulomatous
disease. Cross et al. (1996) tabulated 123 mutations in the CYBB gene
known to cause chronic granulomatous disease. Heyworth et al. (1997)
presented updated tables containing 64 newly identified mutations.

Ariga et al. (1998) concluded that the proportion of sporadic cases of
CGD, i.e., patients in whom the mother is not a carrier, is very low,
and that the proportion of sporadic carriers, i.e., mothers who
inherited a new mutation, is high. These results suggested that the
mutation for the disease originates mainly in male gametes.

Patino et al. (1999) reported the molecular characterization of 7
unrelated kindreds with CGD from Colombia and Brazil. In 6 of these
kindreds, all mothers were carriers; in the seventh, the mutation was de
novo.

Ishibashi et al. (2000) reported a statistical analysis of 229 patients
from 195 families with chronic granulomatous disease in Japan and
described the findings of mutation analysis of 28 and 5 unrelated
patients, respectively, with gp91- and p22-phox deficiency. The ratio of
male to female patients was 6.6/1, the incidence was calculated to be
about 1 in 220,000 births, and the life expectancy of the patients born
in the 1970s was estimated to be about 25 to 30 years. A total of 9
patients from 8 families had been found in Japan with CGD in combination
with retinitis pigmentosa. Three families had a large deletion involving
the CYBB gene. One patient had X-CDG in combination with McLeod syndrome
(300842).

CYTOGENETICS

Kumatori et al. (1998) concluded that nonhomologous recombination
between the CYBB gene and a LINE-1 element lies 5-kb upstream of CYBB in
normal persons. They reported a patient with chronic granulomatous
disease who had a 25-kb deletion extending to the 5-prime two-thirds of
CYBB. The 3-prime breakpoint of the deletion was located in exon 7 of
CYBB; the 5-prime breakpoint was in the LINE-1 element. There were no
significant homologies between corresponding normal 5-prime and 3-prime
regions flanking the breakpoint of the patient, so a nonhomologous
recombination was considered the most likely mechanism for the 25-kb
deletion. The analysis also showed that the patient had a novel 30-bp
duplication in the 5-prime flanking region of the deletion point, which
was transmitted by his mother with the deletion. The study suggested
that the deletion occurred in his grandfather.

ANIMAL MODEL

Pollock et al. (1995) created an animal model of X-linked CGD. They used
gene targeting to generate mice with a null allele of the gene that
encodes the 91-kD subunit of the oxidase cytochrome b. Affected
hemizygous male mice lacked phagocyte superoxide production, manifested
an increased susceptibility to infection with Staphylococcus aureus and
Aspergillus fumigatus, and had an altered inflammatory response to
thioglycollate peritonitis. They suggested that the animal model would
be helpful in developing new treatments for CGD and in evaluating the
role of phagocyte-derived oxidants in inflammation.

HISTORY

No abnormality of red cell Kell phenotype (see 110900) was found in 15
Japanese cases of CGD (Ito et al., 1979). It had been suggested that a
defect of blood group precursor in the white cell membrane leads to
deficient activation of NADH dehydrogenase in 1 form of CGD. It turned
out that the cases of CGD with the McLeod phenotype, resulting from
deletion of the Xk locus, represented a contiguous gene syndrome, as
defined by Schmickel (1986), due to deletion of the closely linked CYBB
and Xk loci in Xp21.

Densen et al. (1981) reported a highly informative family in which 4 of
8 brothers had CGD by clinical history and tests of neutrophil function.
All 4 affected brothers had Kell (Kx)-negative neutrophils. The
remaining 4 unaffected brothers were in good health and had normal NBT
tests. However, 1 of the unaffected brothers had Kx-negative neutrophils
that functioned normally. Densen et al. (1981) concluded that closely
linked but distinct genes code for CGD and Kx. In addition, close
linkage of the Xk and Xg loci was demonstrated; no recombinant was found
in this sibship. Although it appears that the coexistence of CGD and the
McLeod syndrome in some patients is due to the deletion of 2 very
closely linked genes, Xk and CGD, Branch et al. (1986) showed that
granulocytes lack red cell Kx antigen. The previous finding of Kx on
white cells was presumably due to contamination of the testing serum by
anti-WBC antibodies of non-Kx specificity.

*FIELD* SA
Biggar (1975); Brzica et al. (1977); Curnutte et al. (1992); D'Amelio
et al. (1984); de Martinville et al. (1985); Dinauer and Orkin (1988);
Dinauer et al. (1987); Edwards (1969); Fikrig et al. (1980); Gabig
and Lefker (1984); Holmes et al. (1967); Horn and Lehrer (1975); Johnston
(1982); Johnston et al. (1975); Klebanoff and Clark (1978); Kontras
et al. (1971); Macher et al. (1982); Marsh et al. (1975); Marsh et
al. (1975); Mills et al. (1980); Nathan et al. (1969); Newburger et
al. (1979); Orkin (1989); Orkin (1987); Schmalzer and Miller (1976);
Segal (1988); Segal (1988); Soothill (1969); Taswell et al. (1977);
Thompson et al. (1969); Wolff et al. (1980)
*FIELD* RF
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90. Schmalzer, E. A.; Miller, D. R.: Chronic granulomatous disease. Prog.
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92. Segal, A. W.: The molecular and cellular pathology of chronic
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93. Segal, A. W.: Variations on the theme of chronic granulomatous
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*FIELD* CS
INHERITANCE:
X-linked 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 protein;
Deficiency or absence of p22-phox (608508) protein;
Negative nitroblue tetrazolium (NBT) reduction test;
Decreased activity of NADPH oxidase

MISCELLANEOUS:
Onset usually in first decade;
'Variant' form of X-linked CGD retains residual cytochrome b(-245);
Four types of CGD with basically identical clinical phenotypes;
X-linked recessive cytochrome b-negative CGD;
Autosomal recessive cytochrome b-negative CGD (233690);
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) beta subunit gene (CYBB,
300481.0001)

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

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

*FIELD* ED
joanna: 09/02/2011
joanna: 5/27/2011
joanna: 3/15/2004
ckniffin: 3/15/2004
ckniffin: 3/11/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 5/15/2006
Victor A. McKusick - updated: 1/7/2005
Cassandra L. Kniffin - reorganized: 3/12/2004
Cassandra L. Kniffin - updated: 3/11/2004
Victor A. McKusick - updated: 4/7/2003
Victor A. McKusick - updated: 2/12/2003
Victor A. McKusick - updated: 8/27/2002
Victor A. McKusick - updated: 10/9/2001
Deborah L. Stone - updated: 9/11/2001
Victor A. McKusick - updated: 9/5/2001
Victor A. McKusick - updated: 4/6/2001
Victor A. McKusick - updated: 11/2/2000
Victor A. McKusick - updated: 6/12/2000
Victor A. McKusick - updated: 3/24/1999
Ada Hamosh - updated: 3/9/1999
Victor A. McKusick - updated: 1/12/1999
Victor A. McKusick - updated: 11/30/1998
Victor A. McKusick - updated: 6/23/1998
Victor A. McKusick - updated: 3/30/1998
Iosif W. Lurie - updated: 1/8/1997
Stylianos E. Antonarakis - updated: 7/8/1996

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mgross: 12/16/2011
wwang: 5/24/2011
terry: 5/19/2011
ckniffin: 5/12/2011
alopez: 5/2/2011
alopez: 4/18/2011
carol: 6/29/2010
ckniffin: 9/22/2009
wwang: 9/9/2009
alopez: 7/14/2009
terry: 3/27/2009
wwang: 5/24/2006
ckniffin: 5/15/2006
terry: 3/22/2006
alopez: 1/7/2005
carol: 10/28/2004
alopez: 9/9/2004
carol: 3/15/2004
ckniffin: 3/15/2004
carol: 3/12/2004
terry: 3/12/2004
ckniffin: 3/11/2004
tkritzer: 2/3/2004
mgross: 1/30/2004
tkritzer: 4/7/2003
carol: 2/27/2003
tkritzer: 2/24/2003
terry: 2/12/2003
tkritzer: 9/6/2002
tkritzer: 9/5/2002
tkritzer: 8/30/2002
terry: 8/27/2002
mgross: 7/12/2002
carol: 3/13/2002
carol: 11/6/2001
mcapotos: 10/19/2001
terry: 10/9/2001
carol: 9/11/2001
carol: 9/10/2001
terry: 9/5/2001
mcapotos: 4/16/2001
mcapotos: 4/9/2001
terry: 4/6/2001
alopez: 3/20/2001
mcapotos: 11/16/2000
mcapotos: 11/14/2000
terry: 11/2/2000
carol: 9/13/2000
mcapotos: 7/20/2000
mcapotos: 6/27/2000
terry: 6/12/2000
mgross: 4/2/1999
terry: 3/24/1999
alopez: 3/12/1999
alopez: 3/9/1999
carol: 1/15/1999
carol: 1/14/1999
terry: 1/12/1999
dkim: 12/15/1998
carol: 12/2/1998
terry: 11/30/1998
carol: 6/25/1998
terry: 6/23/1998
terry: 6/4/1998
alopez: 3/30/1998
terry: 3/25/1998
terry: 3/13/1997
terry: 3/6/1997
jenny: 3/4/1997
jenny: 1/21/1997
jenny: 1/8/1997
mark: 1/3/1997
terry: 11/6/1996
mark: 7/8/1996
carol: 2/13/1995
terry: 7/18/1994
jason: 6/28/1994
mimadm: 5/18/1994
warfield: 4/20/1994
pfoster: 3/30/1994