Cytochrome b-245, alpha polypeptide

CYBA
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCYBA, p22-PHOX, Cytochrome b-245, alpha polypeptide, cytochrome b-245 alpha chain
External IDsMGI: 1316658 HomoloGene: 80 GeneCards: CYBA
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

1535

13057

Ensembl

ENSG00000051523

ENSMUSG00000006519

UniProt

P13498

Q61462

RefSeq (mRNA)

NM_000101

NM_001301284
NM_007806

RefSeq (protein)

NP_000092

NP_001288213
NP_031832

Location (UCSC)Chr 16: 88.64 – 88.65 MbChr 8: 122.42 – 122.43 Mb
PubMed search[1][2]
Wikidata
View/Edit HumanView/Edit Mouse

Cytochrome b-245 light chain is a protein that in humans is encoded by the CYBA gene involved in superoxide production and phagocytosis.[3]

Cytochrome b-245 is composed of a light chain (alpha) and a heavy chain (beta). This gene encodes the light, alpha subunit, which has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Mutations in this gene are associated with autosomal recessive chronic granulomatous disease (CGD), which is characterized by the failure of activated phagocytes to generate superoxide, which is important for the microbicidal activity of these cells.[4]

Discovery

The p22phox protein (phox for phagocytic oxidase) was first identified in 1987 during the purification of the cytochrome b-245mv from human neutrophils.[5] A few years before, this low-potential cytochrome b, also called cytochrome b558 (cytb) because of its spectral properties, was demonstrated as the major component of the microbicidal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytes.[6][7][8] Cytb, the redox element of the NADPH oxidase complex, is a membrane heterodimer composed of two subunits: p22phox (also called the alpha or small subunit or the light chain of the cytb) and gp91phox (renamed NOX2 in the 2000s) or the beta or heavy chain or large subunit. By screening a cDNA library constructed from human promyelocytic leukemia cells, Parkos et al. isolated a cDNA corresponding to the light chain of cytb.[9] The importance of the role of p22phox was evidenced by the discovery of autosomal recessive chronic granulomatous disease caused by mutations in CYBA and leading to the absence of cytb expression in phagocytes.[3]

Gene

The human CYBA gene (OMIM number 233690) encoding the p22phox protein is located on the long arm of chromosome 16 at position 24 (16q24: 88,643,288 to 88,651,084, OMIM 608508), containing 6 exons, 5 introns and spanning 8.5kb (Fig. 1). An update of the promoter region of CYBA contains TATA, CCAC boxes, Sp1, -interferon, and nuclear factor B sites.[10] The p22phox cDNA was also cloned in rat vascular smooth muscle cells (VSMCs) and showed that the rat gene was homologous to both human and mouse genes.[11] P22phox human mRNA is 0.8 kb and has a constitutive expression in a variety of cell types. P22phox expression is not related to the NOX2 transcript expression, suggesting that both subunits have an independent transcription process.[12][13]

Protein structure and function

P22phox is a transmembrane protein that contains 195 amino acids and that has a molecular mass of 22.0 kDa. It associates with NOX2 and with NOX1, NOX3 and NOX4 in a 1:1 complex and has a ubiquitous expression. The main physiological role of p22phox is to contribute to the maturation and the stabilization of the heterodimer that it forms with NOX enzymes (NOX1–4) in order to produce reactive oxygen species (ROS). Association of NOXs with p22phox in the late endoplasmic reticulum seems to be a prerequisite for the localization of the heterodimer to specific membrane compartments such as perinuclear vesicles for NOX4 and plasma membranes in the case of NOX1, 2 and 3.[14][15][16][17] The importance of some sequences of p22phox for its interaction with NOXs has been highlighted.[18] The hydropathic profile of p22phox deduced from the gene sequence is compatible with at least two (possibly three or four) transmembrane passages.[19][20][21][22][23][24][25] However, the most probable are the two or four transmembrane-spanning models because they are compatible with a cytosolic location of both the N- and the C-terminal tail of p22phox. A polyproline-rich region (PRR) (K149 to E162 sequence) in the C-terminus of p22phox contains a consensus motif PxxP that interacts with the SH3 (SRC homology 3) domains of p47phox during NADPH oxidase assembly in phagocytes.[21][26][27][28] This PRR-rich sequence also interacts with the cytosolic organizer NOXO1 homologs to p47phox expressed in nonphagocytic cells, during the activation of NADPH oxidases (NOX1, NOX2 and NOX3), except for NOX4, which is constitutively expressed.[29][30] It is also interesting to underline that phosphorylation of Thr147 close to the PRR region of p22phox enhances NADPH oxidase activity by promoting p47phox binding in phagocytes.[31] ROSs generated by NOX2-p22phox (or cytb) in the phagocytes are microbicide and are able to kill microorganisms during infections. P22phox associated with NOX2 is also found in brain and especially in microglia. Anarchic ROS production by these cells is involved in the pathological process of degenerative diseases.[32][33] P22phox can be associated with NOX1, NOX3 and NOX4 in several cells and tissues, but the level of ROS production is far lower than those produced in phagocytes by cytb. In this case ROSs are considered as signaling messengers rather than toxic products. Excessive ROS generation by NOX enzymes has been linked to a range of diseases including cardiovascular diseases such as atherosclerosis and hypertension, diabetes, neurodegenerative disease and ischemia/reperfusion injury.[32] NOX1, NOX2 and NOX4, which require p22phox to be functional, are important contributors of ROS in tissues and especially vascular cells. Therefore, the variability of ROS production by NOXs could influence the risk of such diseases, although increased oxidative stress by p22phox overexpression has not been functionally characterized or attributed to a particular NOX family member.

Clinical relevance of mutations

Mutations in CYBA or CYBB, encoding p22phox or NOX2, respectively, lead to Chronic granulomatous disease because of the absence of cytb in both cases.[12] This means that the synthesis of both subunits is essential for the maturation of cytb.[34] CGD is a rare inherited disorder in which phagocytic cells are unable to kill pathogens during an infection. Patients suffer from severe and recurrent infections early in childhood. Actually, the main treatment is antibiotic and antifungal prophylaxis. Allogenic bone marrow transplantation is possible and genetic therapy is currently under development.[35] The most frequent CGD form is X-linked CGD caused by mutations in CYBB (60% of cases).[36] Mutations in the CYBA gene encoding p22phox are extremely rare (about 6%) and lead to AR-CGD220. However, in countries such as Turkey, Tunisia, Morocco and Jordan AR inheritance can be the predominant form because of the high rate of consanguinity.[37][38][39][40] As of 2010, 55 different mutations of CYBA have been identified.[41] Most CYBA mutations result in the absence of p22phox expression (AR-CGD220). The only missense mutation leading to a normal expression of a nonfunctional p22phox protein is Pro156Gln (AR-CGD22+) located in the potential cytosolic C-terminal tail of p22phox.[42] This mutation in the PRR of p22phox disrupted the interaction between p22phox and p47phox, confirming the importance of this domain in the oxidase activation in neutrophils. Since p22phox is ubiquitous and associated with different NOXs, it could be logical that CGD patients suffer from the consequences of the absence of p22phox expression in tissues. However it is far from being evident. One possibility could be that the humans may be able to compensate for the absence of p22phox and/or NOXs in cells and tissues other than phagocytes. Given the rarity of the AR-CGD220 forms, information on the severity of this type of CGD is difficult to establish. A relationship between the presence of residual ROS production and the survival of CGD patients has been found.[43] In case of CYBA mutations leading to the absence of p22phox, NOX2 expression is also absent and disables cytochrome b558, the redox element of the NADPH oxidase complex. Therefore, these mutations behave similarly to severe X-CGD. The molecular and phenotypic characterization of a p22phox-deficient mouse strain with the Tyr121His missense mutation in CYBA has been described.[44] The p22phox deficiency results in the clinical and biological characteristics of CGD as well as a severe balance disorder in these mice. As the site of p22phox expression is in the inner ear, p22phox has been proposed as being involved in the control of vestibular organogenesis. In addition, mutations of NOX3 in head-tilt mice were associated with vestibular defects.[45][46] Yet the in vivo relevance of p22phox for NOX3 function remains uncertain because AR-CGD220 patients do not suffer from vestibular dysfunction (personal data). One possibility could be that the human brain may be able to compensate the balance defect. In Matsumoto Eosinophilia Shinshu (MES) rats a loss-of-function mutation in CYBA was responsible for spontaneous and severe blood eosinophilia.[47] These rats suffered from a balance defect due to a leak of otoconia in the inner ear, like nmf333 mice. In addition, MES rats retained normal innate immune defense against Staphylococcus aureus infection probably because of the hypereosinophilia. However, the mechanisms by which CYBA mutations lead to eosinophilia remain unknown.

Clinical relevance of single-nucleotide polymorphisms

Contrary to CYBB, CYBA supports a relatively high number of single-nucleotide polymorphisms (SNPs) that could influence the level of ROS generation. These SNPs were mainly associated with cardiovascular diseases such as hypertension,[48] coronary artery disease (CAD), coronary heart disease (CHD)[49][50] and also cerebral ischemic diseases.[51][52] The first and most widely studied is the C242T polymorphism is located in exon 4 at position 214 from the ATG and resulting in a non conservative His72 substitution for a Tyr.[3] Inoue et al. first found that the T allele of the C242 polymorphism might have a protective effect against CAD.[53] Despite some evidence of the effect of this polymorphism on ROS generation at the cellular level, the association of the CYBA C242T polymorphism with cardiovascular diseases has been widely reported but with conflicting results.[50] Single SNP analysis may explain the discrepancies among CYBA association studies. A global approach such as haplotype analysis is probably a better approach to understand the impact of CYBA genetic variability on diseases.[54][55][56] CYBA variants together with polymorphism analysis of lipid metabolism or stress oxidant pathway genes are of great interest as well.[57][58][59] However, for future investigations regarding the effect of these polymorphisms, it is crucial that the number of patients under study provide sufficient statistical power. In addition, genetics studies that include control of external factors should be extremely informative. Finally, since 2010 nine Chinese meta-analyses of the C242T polymorphism have been published in relation with CAD,[60][61][62][63][64] hypertension[48] atherosclerosis or diabetes and its complications[52] and ischemic cerebrovascular diseases.[51][52] The results from these meta-analyses were controversial. Several factors could influence these data: the search strategy, the identification of relevant studies (publication bias), the statistical analysis including a sufficient sampling, the prevalence of the studied polymorphism in the studied population [minor allele frequency (MAF)] and the type of population (population-based or not, for example). Results of these meta-analyses need to be confirmed with larger samples. In addition, a meta-analysis based on genome-wide association study data will be of great interest in the future.

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. 1 2 3 Dinauer MC, Pierce EA, Bruns GA, Curnutte JT, Orkin SH (Nov 1990). "Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease". The Journal of Clinical Investigation. 86 (5): 1729–37. PMC 296926 Freely accessible. PMID 2243141. doi:10.1172/JCI114898.
  4. ↑ "Entrez Gene: CYBA cytochrome b-245, alpha polypeptide".
  5. ↑ Parkos CA, Allen RA, Cochrane CG, Jesaitis AJ (Sep 1987). "Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000". The Journal of Clinical Investigation. 80 (3): 732–42. PMC 442297 Freely accessible. PMID 3305576. doi:10.1172/JCI113128.
  6. ↑ Segal AW, Jones OT (Nov 1978). "Novel cytochrome b system in phagocytic vacuoles of human granulocytes". Nature. 276 (5687): 515–7. PMID 723935. doi:10.1038/276515a0.
  7. ↑ Segal AW, Harper A, Garcia R, Jones OT, Cross AR (1981). "The nature and function of the microbicidal oxidase system of neutrophils". Bulletin Européen De Physiopathologie Respiratoire. 17 Suppl: 187–91. PMID 7248569.
  8. ↑ Harper AM, Dunne MJ, Segal AW (Apr 1984). "Purification of cytochrome b-245 from human neutrophils". The Biochemical Journal. 219 (2): 519–27. PMC 1153509 Freely accessible. PMID 6331390. doi:10.1042/bj2190519.
  9. ↑ Parkos CA, Dinauer MC, Walker LE, Allen RA, Jesaitis AJ, Orkin SH (May 1988). "Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b". Proceedings of the National Academy of Sciences of the United States of America. 85 (10): 3319–23. PMC 280200 Freely accessible. PMID 3368442. doi:10.1073/pnas.85.10.3319.
  10. ↑ Moreno MU, San José G, Orbe J, Páramo JA, Beloqui O, Díez J, Zalba G (May 2003). "Preliminary characterisation of the promoter of the human p22(phox) gene: identification of a new polymorphism associated with hypertension". FEBS Letters. 542 (1-3): 27–31. PMID 12729892. doi:10.1016/s0014-5793(03)00331-4.
  11. ↑ Fukui T, Lassègue B, Kai H, Alexander RW, Griendling KK (Oct 1995). "Cytochrome b-558 alpha-subunit cloning and expression in rat aortic smooth muscle cells". Biochimica et Biophysica Acta. 1231 (3): 215–9. PMID 7578211. doi:10.1016/0005-2728(95)00098-4.
  12. 1 2 Parkos CA, Dinauer MC, Jesaitis AJ, Orkin SH, Curnutte JT (May 1989). "Absence of both the 91kD and 22kD subunits of human neutrophil cytochrome b in two genetic forms of chronic granulomatous disease". Blood. 73 (6): 1416–20. PMID 2713485.
  13. ↑ Cheng G, Cao Z, Xu X, van Meir EG, Lambeth JD (May 2001). "Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5". Gene. 269 (1-2): 131–40. PMID 11376945. doi:10.1016/s0378-1119(01)00449-8.
  14. ↑ Ambasta RK, Kumar P, Griendling KK, Schmidt HH, Busse R, Brandes RP (2004). "Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase". The Journal of Biological Chemistry. 279 (44): 45935–41. PMID 15322091. doi:10.1074/jbc.M406486200.
  15. ↑ Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC, Knaus UG (2006). "Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases". Cellular Signalling. 18 (1): 69–82. PMID 15927447. doi:10.1016/j.cellsig.2005.03.023.
  16. ↑ Nakano Y, Banfi B, Jesaitis AJ, Dinauer MC, Allen LA, Nauseef WM (2007). "Critical roles for p22phox in the structural maturation and subcellular targeting of Nox3". The Biochemical Journal. 403 (1): 97–108. PMC 1828898 Freely accessible. PMID 17140397. doi:10.1042/BJ20060819.
  17. ↑ von Löhneysen K, Noack D, Wood MR, Friedman JS, Knaus UG (2010). "Structural insights into Nox4 and Nox2: motifs involved in function and cellular localization". Molecular and Cellular Biology. 30 (4): 961–75. PMC 2815567 Freely accessible. PMID 19995913. doi:10.1128/MCB.01393-09.
  18. ↑ von Löhneysen K, Noack D, Jesaitis AJ, Dinauer MC, Knaus UG (Dec 2008). "Mutational analysis reveals distinct features of the Nox4-p22 phox complex". The Journal of Biological Chemistry. 283 (50): 35273–82. PMC 2596391 Freely accessible. PMID 18849343. doi:10.1074/jbc.M804200200.
  19. ↑ Imajoh-Ohmi S, Tokita K, Ochiai H, Nakamura M, Kanegasaki S (Jan 1992). "Topology of cytochrome b558 in neutrophil membrane analyzed by anti-peptide antibodies and proteolysis". The Journal of Biological Chemistry. 267 (1): 180–4. PMID 1730586.
  20. ↑ Burritt JB, Busse SC, Gizachew D, Siemsen DW, Quinn MT, Bond CW, Dratz EA, Jesaitis AJ (Sep 1998). "Antibody imprint of a membrane protein surface. Phagocyte flavocytochrome b". The Journal of Biological Chemistry. 273 (38): 24847–52. PMID 9733789. doi:10.1074/jbc.273.38.24847.
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  26. ↑ Groemping Y, Lapouge K, Smerdon SJ, Rittinger K (May 2003). "Molecular basis of phosphorylation-induced activation of the NADPH oxidase". Cell. 113 (3): 343–55. PMID 12732142. doi:10.1016/s0092-8674(03)00314-3.
  27. ↑ Ogura K, Nobuhisa I, Yuzawa S, Takeya R, Torikai S, Saikawa K, Sumimoto H, Inagaki F (Feb 2006). "NMR solution structure of the tandem Src homology 3 domains of p47phox complexed with a p22phox-derived proline-rich peptide". The Journal of Biological Chemistry. 281 (6): 3660–8. PMID 16326715. doi:10.1074/jbc.M505193200.
  28. ↑ Zhu Y, Marchal CC, Casbon AJ, Stull N, von Löhneysen K, Knaus UG, Jesaitis AJ, McCormick S, Nauseef WM, Dinauer MC (Oct 2006). "Deletion mutagenesis of p22phox subunit of flavocytochrome b558: identification of regions critical for gp91phox maturation and NADPH oxidase activity". The Journal of Biological Chemistry. 281 (41): 30336–46. PMID 16895900. doi:10.1074/jbc.M607191200.
  29. ↑ Sumimoto H (Jul 2008). "Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species". The FEBS Journal. 275 (13): 3249–77. PMID 18513324. doi:10.1111/j.1742-4658.2008.06488.x.
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  31. ↑ Lewis EM, Sergeant S, Ledford B, Stull N, Dinauer MC, McPhail LC (Jan 2010). "Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding". The Journal of Biological Chemistry. 285 (5): 2959–67. PMC 2823407 Freely accessible. PMID 19948736. doi:10.1074/jbc.M109.030643.
  32. 1 2 Bedard K, Krause KH (Jan 2007). "The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology". Physiological Reviews. 87 (1): 245–313. PMID 17237347. doi:10.1152/physrev.00044.2005.
  33. ↑ Krause KH, Lambeth D, Krönke M (Jul 2012). "NOX enzymes as drug targets". Cellular and Molecular Life Sciences. 69 (14): 2279–82. PMC 3383960 Freely accessible. PMID 22585058. doi:10.1007/s00018-012-1006-5.
  34. ↑ Beaumel S, Grunwald D, Fieschi F, Stasia MJ (Dec 2014). "Identification of NOX2 regions for normal biosynthesis of cytochrome b558 in phagocytes highlighting essential residues for p22phox binding". The Biochemical Journal. 464 (3): 425–37. PMID 25252997. doi:10.1042/BJ20140555.
  35. ↑ van den Berg JM, van Koppen E, Ahlin A, Belohradsky BH, Bernatowska E, Corbeel L, Español T, Fischer A, Kurenko-Deptuch M, Mouy R, Petropoulou T, Roesler J, Seger R, Stasia MJ, Valerius NH, Weening RS, Wolach B, Roos D, Kuijpers TW (2009). "Chronic granulomatous disease: the European experience". PloS One. 4 (4): e5234. PMC 2668749 Freely accessible. PMID 19381301. doi:10.1371/journal.pone.0005234.
  36. ↑ Roos D, Kuhns DB, Maddalena A, Roesler J, Lopez JA, Ariga T, Avcin T, de Boer M, Bustamante J, Condino-Neto A, Di Matteo G, He J, Hill HR, Holland SM, Kannengiesser C, Köker MY, Kondratenko I, van Leeuwen K, Malech HL, Marodi L, Nunoi H, Stasia MJ, Ventura AM, Witwer CT, Wolach B, Gallin JI (Oct 2010). "Hematologically important mutations: X-linked chronic granulomatous disease (third update)". Blood Cells, Molecules & Diseases. 45 (3): 246–65. PMC 4360070 Freely accessible. PMID 20729109. doi:10.1016/j.bcmd.2010.07.012.
  37. ↑ El Kares R, Barbouche MR, Elloumi-Zghal H, Bejaoui M, Chemli J, Mellouli F, Tebib N, Abdelmoula MS, Boukthir S, Fitouri Z, M'Rad S, Bouslama K, Touiri H, Abdelhak S, Dellagi MK (2006). "Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia". Journal of Human Genetics. 51 (10): 887–95. PMID 16937026. doi:10.1007/s10038-006-0039-8.
  38. ↑ Bakri FG, Martel C, Khuri-Bulos N, Mahafzah A, El-Khateeb MS, Al-Wahadneh AM, Hayajneh WA, Hamamy HA, Maquet E, Molin M, Stasia MJ (Mar 2009). "First report of clinical, functional, and molecular investigation of chronic granulomatous disease in nine Jordanian families". Journal of Clinical Immunology. 29 (2): 215–30. PMID 18773283. doi:10.1007/s10875-008-9243-y.
  39. ↑ Köker MY, Camcıoğlu Y, van Leeuwen K, Kılıç SŞ, Barlan I, Yılmaz M, Metin A, de Boer M, Avcılar H, Patıroğlu T, Yıldıran A, Yeğin O, Tezcan I, Sanal Ö, Roos D (Nov 2013). "Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients". The Journal of Allergy and Clinical Immunology. 132 (5): 1156–1163.e5. PMID 23910690. doi:10.1016/j.jaci.2013.05.039.
  40. ↑ Bousfiha AA, Jeddane L, El Hafidi N, Benajiba N, Rada N, El Bakkouri J, Kili A, Benmiloud S, Benhsaien I, Faiz I, Maataoui O, Aadam Z, Aglaguel A, Baba LA, Jouhadi Z, Abilkassem R, Bouskraoui M, Hida M, Najib J, Alj HS, Ailal F (May 2014). "First report on the Moroccan registry of primary immunodeficiencies: 15 years of experience (1998-2012)". Journal of Clinical Immunology. 34 (4): 459–68. PMID 24619622. doi:10.1007/s10875-014-0005-8.
  41. ↑ Roos D, Kuhns DB, Maddalena A, Bustamante J, Kannengiesser C, de Boer M, van Leeuwen K, Köker MY, Wolach B, Roesler J, Malech HL, Holland SM, Gallin JI, Stasia MJ (Apr 2010). "Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update)". Blood Cells, Molecules & Diseases. 44 (4): 291–9. PMC 4568122 Freely accessible. PMID 20167518. doi:10.1016/j.bcmd.2010.01.009.
  42. ↑ Leusen JH, Bolscher BG, Hilarius PM, Weening RS, Kaulfersch W, Seger RA, Roos D, Verhoeven AJ (Dec 1994). "156Pro-->Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox". The Journal of Experimental Medicine. 180 (6): 2329–34. PMC 2191792 Freely accessible. PMID 7964505. doi:10.1084/jem.180.6.2329.
  43. ↑ Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, Uzel G, DeRavin SS, Priel DA, Soule BP, Zarember KA, Malech HL, Holland SM, Gallin JI (Dec 2010). "Residual NADPH oxidase and survival in chronic granulomatous disease". The New England Journal of Medicine. 363 (27): 2600–10. PMC 3069846 Freely accessible. PMID 21190454. doi:10.1056/NEJMoa1007097.
  44. ↑ Nakano Y, Longo-Guess CM, Bergstrom DE, Nauseef WM, Jones SM, Bánfi B (Mar 2008). "Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice". The Journal of Clinical Investigation. 118 (3): 1176–85. PMC 2248803 Freely accessible. PMID 18292807. doi:10.1172/JCI33835.
  45. ↑ Bánfi B, Malgrange B, Knisz J, Steger K, Dubois-Dauphin M, Krause KH (Oct 2004). "NOX3, a superoxide-generating NADPH oxidase of the inner ear". The Journal of Biological Chemistry. 279 (44): 46065–72. PMID 15326186. doi:10.1074/jbc.M403046200.
  46. ↑ Paffenholz R, Bergstrom RA, Pasutto F, Wabnitz P, Munroe RJ, Jagla W, Heinzmann U, Marquardt A, Bareiss A, Laufs J, Russ A, Stumm G, Schimenti JC, Bergstrom DE (Mar 2004). "Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase". Genes & Development. 18 (5): 486–91. PMC 374230 Freely accessible. PMID 15014044. doi:10.1101/gad.1172504.
  47. ↑ Mori M, Li G, Hashimoto M, Nishio A, Tomozawa H, Suzuki N, Usami S, Higuchi K, Matsumoto K (Sep 2009). "Pivotal Advance: Eosinophilia in the MES rat strain is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba)". Journal of Leukocyte Biology. 86 (3): 473–8. PMID 19406829. doi:10.1189/jlb.1108715.
  48. 1 2 Qin YW, Peng J, Liang BY, Su L, Chen Q, Xie JJ, Gu L (2013). "The A930G polymorphism ofP22phox (CYBA) gene but not C242T variation is associated with hypertension: a meta-analysis". PloS One. 8 (12): e82465. PMC 3857280 Freely accessible. PMID 24349292. doi:10.1371/journal.pone.0082465.
  49. ↑ San José G, Fortuño A, Beloqui O, Díez J, Zalba G (Feb 2008). "NADPH oxidase CYBA polymorphisms, oxidative stress and cardiovascular diseases". Clinical Science. 114 (3): 173–82. PMID 18184111. doi:10.1042/CS20070130.
  50. 1 2 Moreno MU, Zalba G (Jun 2010). "CYBA gene variants as biomarkers for coronary artery disease". Drug News & Perspectives. 23 (5): 316–24. PMID 20603655. doi:10.1358/dnp.2010.23.5.1437711.
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