Alternative titles; symbols
HGNC Approved Gene Symbol: CYBA
Cytogenetic location: 16q24.2 Genomic coordinates (GRCh38) : 16:88,643,289-88,651,053 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.2 | Chronic granulomatous disease 4, autosomal recessive | 233690 | Autosomal recessive | 3 |
The CYBA gene encodes the alpha subunit, also known as the light chain, of cytochrome b(-245), which is a component of the NADPH oxidase (NOX) complex responsible for the respiratory burst in phagocytes.
The CYBB gene (300481) is an X-linked gene which encodes the cytochrome b beta subunit, also known as the heavy chain.
Dinauer et al. (1990) and Schapiro et al. (1991) referred to the 22-kD gene product as p22-phox (for phagocyte oxidase). De Boer et al. (1992) referred to the product of the CYBA gene as the alpha subunit of cytochrome b(558) or p22-phox. They mentioned an international agreement on designations.
By screening a cDNA library constructed from human promyelocytic leukemia cells, Parkos et al. (1988) isolated a cDNA corresponding to the light chain of cytochrome b. The cDNA encodes a 195-amino acid protein with a high proline content (10%) and a molecular mass of 22 kD. A database search showed that a 31-residue region of the protein is 39% identical to a corresponding region of the heme-bearing subunit (polypeptide I) of mitochondrial cytochrome c oxidase (MTCO1; 516030). Northern blot analysis detected a 0.8-kb mRNA transcript in all cell lines tested, including phagocytes, hepatic cells, endothelial cells, B cells, and erythroleukemic cells, but the 22-kD protein was barely detectable in the nonphagocytic cells, suggesting a block in translation in these cells. The stable protein was detected only in phagocytic cells that were also expressing the larger cytochrome b subunit, p91-phox. Parkos et al. (1988) concluded that the large subunit may play a role in regulating the assembly of the heterodimeric cytochrome b.
Fukui et al. (1995) isolated a cDNA for the cytochrome b alpha subunit (p22-phox) of the NADPH oxidase in rat vascular smooth muscle cells (VSMCs) and showed that the rat gene is homologous to both the human and mouse genes.
Dinauer et al. (1990) determined that the CYBA gene contains 6 exons and spans 8.5 kb.
Using Southern blot analysis of DNA from human-rodent somatic cell hybrids, Bu-Ghanim et al. (1990) demonstrated that the alpha subunit is encoded by a single locus (CYBA) on chromosome 16. By a combination of Southern blot analysis of somatic cell hybrids and in situ hybridization, Dinauer et al. (1990) mapped the CYBA gene to 16q24.
By genomic sequence analysis, Powell et al. (2002) mapped the CYBA gene to chromosome 16q24.3.
Ushio-Fukai et al. (1996) provided evidence that p22-phox is a critical component of the superoxide-generating vascular NADH/NADPH oxidase. They stably transfected antisense p22-phox cDNA into rat VSMCs and showed that this results in decreased cytochrome-b content and superoxide production.
Superoxide anion (O2-) formation occurs in phagocytic cells, such as neutrophils, macrophages, and monocytes, and is important for the microbicidal activity of these cells. The production of superoxide anion is not limited to these cell types, however, and has been implicated in the pathogenesis of both hypertension and atherosclerosis (Alexander, 1995).
Yazdanpanah et al. (2009) identified riboflavin kinase (RFK, formerly known as flavokinase; 613010) as a TNFR1 (191190)-binding protein that physically and functionally couples TNFR1 to NADPH oxidase (300225). In mouse and human cells, RFK binds to both the TNFR1 death domain and to p22(phox), the common subunit of NADPH oxidase isoforms. RFK-mediated bridging of TNFR1 and p22(phox) is a prerequisite for TNF-induced but not for Toll-like receptor (see 601194)-induced reactive oxygen species (ROS) production. Exogenous flavin mononucleotide or FAD was able to substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient cells. RFK is rate-limiting in the synthesis of FAD, an essential prosthetic group of NADPH oxidase. Yazdanpanah et al. (2009) concluded that TNF, through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase.
By microscopic analyses of transfected mouse macrophages and HEK293T cells, Thomas et al. (2017) demonstrated that Eros (CYBC1; 618334) colocalized in the endoplasmic reticulum (ER) with gp91phox and p22phox. Coimmunoprecipitation analysis showed that Eros interacted directly with gp91phox. Based on studies of neutrophils and macrophages from Eros -/- mice, the authors found that Eros was required for expression of gp91phox and p22phox, suggesting that Eros controls gp91phx and p22phox degradation in the ER.
Chronic Granulomatous Disease, Autosomal Recessive, 4
In 3 patients with autosomal recessive cytochrome b-negative chronic granulomatous disease (CGD4; 233690), Dinauer et al. (1990) identified 4 mutations in the CYBA gene (608508.0001-608508.0004).
Yamada et al. (2000) performed mutation analysis on 3 female patients with cytochrome b-negative CGD4 and found 2 novel mutations in the CYBA gene. One patient with a severe phenotype had a homozygous nonsense mutation in exon 1 (608508.0009); the other 2 patients with mild phenotypes shared the same homozygous missense mutation in exon 2 (608508.0010). The latter 2 patients, but not the first, were demonstrated to have detectable p22-phox expression and significant granulocyte respiratory burst activity, consistent with the milder phenotype.
Teimourian et al. (2008) identified homozygous mutations or deletions in the CYBA gene (see, e.g., 608508.0012) in 8 patients from 7 unrelated consanguineous Iranian families with cytochrome b-negative CGD4. Patients had a clinical history of recurrent severe infections, including pneumonia, lymphadenitis, liver abscesses, and pyodermatitis. Four of the patients presented before 1 year of age.
Polymorphisms
Parkos et al. (1988) described a 242C-T polymorphism of the CYBA gene causing a his72-to-tyr change (rs4673; 608508.0008). Bedard et al. (2009) noted that the 242C-T SNP is also referred to as 214T-C (Y72H) based on numbering from the ATG codon.
Inoue et al. (1998) reported that the presence of the 242T polymorphism was associated with reduced risk of coronary artery disease (CAD) in Japanese. This was significant since patients with CAD have impaired endothelial function in part due to an increase in vascular oxidant stress.
Li et al. (1999) studied the frequency of the 242T polymorphism in 252 U.S. patients (83% Caucasian) who underwent angiography for the diagnosis of CAD. The prevalence of the 242T allele was not different in 149 patients with CAD compared to 103 patients with angiographically normal coronary arteries. There were also no significant differences in coronary epicardial or microvascular responses to acetylcholine or sodium nitroprusside between the groups of patients with or without the 242T allele. In the overall study population of 252 patients, the CC genotype was found in 39%, TC in 45%, and TT in 16%, giving a T allele frequency of 0.34 in patients with normal coronary arteries and 0.42 in CAD patients, with a trend in the direction opposite to that observed in the Japanese population by Inoue et al. (1998). The frequency of the T allele was nearly 4 times higher in the U.S. population than in the Japanese population.
Nakano et al. (2008) found that induced-mutant nmf333 mice were deficient in p22-phox protein due to a tyr121-to-his (Y121H) mutation in the Cyba gene. Homozygous mutant mice showed chronic granulomatous disease characterized by absence of superoxide production in phagocytes and complete absence of NADPH oxidase activity. The mutant mice were highly susceptible to fatal necrotizing B. cepacia pneumonia. In addition, mutant mice showed a severe balance disorder associated with complete absence of otoconia in the utricles and saccules of the inner ear. Transgenic expression of wildtype Cyba rescued both phenotypes. Studies on wildtype mice found Cyba expression in the endolymphatic ducts of the embryonic inner ear, which decreased by postnatal day 12. Based on these findings, Nakano et al. (2008) proposed that NOX activity in the endolymph of the embryonic inner ear regulates local ionic conditions and pH, which may favor the crystallization of calcium carbonate and thereby promote the formation of otoconia. However, the authors noted that balance disorders had not been described in humans with CYBA-associated disease.
In a patient with autosomal recessive cytochrome b-negative CGD-4 (CGD4; 233690), whose parents were first cousins, Dinauer et al. (1990) found homozygosity for a large deletion, approximately 10 kb, in the CYBA gene that removed all but the extreme 5-prime coding sequence of the CYBA gene. The patient had originally been reported by Baehner and Nathan (1968).
In a patient with autosomal recessive cytochrome b-negative CGD (CGD4; 233690), Dinauer et al. (1990) identified compound heterozygous mutations in the CYBA gene: a 1-bp deletion (c.272delC), resulting in a frameshift and premature termination, and a c.297G-A transition, resulting in an arg90-to-gln (R90Q) substitution (608508.0003). The patient had previously been reported by Curnutte et al. (1987).
For discussion of the arg90-to-gln (R90Q) mutation in the CYBA gene that was found in compound heterozygous state in a patient with autosomal recessive cytochrome b-negative CGD (CGD4; 233690) by Dinauer et al. (1990), see 608508.0002.
De Boer et al. (1992) reported 3 patients with cytochrome b-negative CGD from 1 family with first-cousin parents who were homozygous for the R90Q mutation.
In a patient with autosomal recessive cytochrome b-negative CGD (CGD4; 233690), whose parents were second cousins, Dinauer et al. (1990) found homozygosity for a 382C-A transversion, resulting in a ser118-to-arg (S118R) substitution.
In a 22-year-old Caucasian female with autosomal recessive cytochrome b-negative CGD (CGD4; 233690) who was the offspring of consanguineous parents, Dinauer et al. (1991) identified a homozygous C-to-A transversion in the CYBA gene that predicted a nonconservative pro156-to-gln (P156Q).
In a patient with autosomal recessive cytochrome b-negative CGD (CGD4; 233690), offspring of first-cousin parents, de Boer et al. (1992) found homozygosity for a 309A-G transition in the CYBA gene, resulting in a nonconservative amino acid replacement, his94-to-arg (H94R).
In a patient with cytochrome b-negative CGD (CGD4; 233690), who was born of first-cousin parents, de Boer et al. (1992) found homozygosity for the absence of exon 4 in the CYBA gene. In this patient, a G-to-A transition was found at position 1 of intron 4; hence, deletion of exon 4 was a result of a splicing error.
Parkos et al. (1988) identified a 242C-T polymorphism (rs4673) in exon 4 of the CYBA gene, leading to a his72-to-tyr (H72Y) substitution. Data on its frequency in Japanese (Inoue et al., 1998) and U.S. (Li et al., 1999) populations have been reported. Bedard et al. (2009) noted that the 242C-T SNP is also referred to as 214T-C (Y72H) based on numbering from the ATG codon.
Reactive Oxygen Species Generation
Bedard et al. (2009) analyzed 7 CYBA polymorphisms and NOX2-dependent reactive oxygen species (ROS) generation in 50 unrelated healthy Caucasian individuals. The authors identified 11 haplotypes, which could be grouped into 7 haplogroups. Only 1 haplogroup, designated 'C' and containing the 214T-C, 521T-C (rs1049254, 549C-T, V174A), and the 3-prime UTR 24G-A (rs1049255, 640A-G) SNPs, had a significant effect on ROS production, showing markedly reduced ROS generation compared to other haplotypes. Although functional analysis demonstrated significantly reduced reporter gene activity with the A allele of the 3-prime UTR SNP 24G-A compared to the G allele (p = 0.0055), haplotype analysis indicated that the observed effect on ROS production was due to the strong contribution of haplotype C. Bedard et al. (2009) suggested that inconsistencies found in published reports might be due to the analysis of individual SNPs rather than haplotypes.
In a 33-year-old Japanese woman with cytochrome b-negative CGD (CGD4; 233690), Yamada et al. (2000) demonstrated homozygosity for a nonsense mutation in exon 1 of the CYBA gene.
In 2 presumably unrelated Japanese patients with mild cytochrome b-negative CGD (CGD4; 233690), Yamada et al. (2000) identified homozygosity for a 98G-A transition in exon 2 of the CYBA gene, resulting in a gly24-to-arg (G24R) substitution. Since the mutation was identified in 2 such patients and since the parents in neither case were related, Yamada et al. (2000) suggested that this may be a relatively common mutation in the Japanese population.
Stasia et al. (2002) used RT-PCR amplification and sequencing to demonstrate a mutation in the p22-PHOX mRNA in a patient with autosomal recessive cytochrome b-negative CGD (CGD4; 233690). The defect was a 179-bp insertion associated with a 21-bp deletion of the beginning of exon 5 at position 315 from the translation start codon of the cDNA. This defect was also detected in the patient's parents. In the genomic DNA of the patient, the molecular defect was a homozygous 36-bp deletion in the linking sequence between intron 4 and exon 5. This genomic deletion corresponded to 15 bp of the 3-prime extremity of intron 4 and 21 bp of the beginning of exon 5 (the same deletion of exon 5 seen in the corresponding mRNA). The splicing mRNA error was attributable to the loss of the AG acceptor site of intron 4 and the utilization of a cryptic splice site with an AG sequence at position 355-356 of intron 4.
In a patient with mild autosomal recessive cytochrome b-negative CGD (CGD4; 233690), Teimourian et al. (2008) identified a homozygous 373G-A transition in exon 6 of the CYBA gene, resulting in an ala125-to-thr (A125T) substitution. The patient presented late at age 18 with pneumonia and liver abscesses, even though there was no detectable p22 protein and no reactive oxygen species production.
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