Alternative titles; symbols
HGNC Approved Gene Symbol: NOX1
Cytogenetic location: Xq22.1 Genomic coordinates (GRCh38) : X:100,843,324-100,874,359 (from NCBI)
By searching EST databases with the sequence of the gp91-phox (CYBB; NOX2; 300481) third transmembrane domain, Banfi et al. (2000) identified a human gene, which they termed NOH1 for 'NADPH oxidase homolog-1.' Banfi et al. (2000) detected 3 RNA products of the NOH1 (NOX1) gene: NOH1L, encoded by 13 exons; NOH1Lv, encoded by 12 exons (exon 11 missing); and NOH1S, a much shorter variant encoded by 6 exons (1 through 4, part of exon 5, and exon 14). In an erratum, Banfi et al. (2005) explained that the NOH1S variant is not a genuine isoform but an artifact most likely due to a stable loop formation of the NOX1 mRNA. NOH1L was detected in colon, uterus, prostate, and colon carcinoma. Hydropathy plots showed a similar profile for NOH1L and gp91-phox, which both contain 4 histidines that constitute the conserved heme-spanning residues of the heme cytochromes.
By searching EST databases for sequences with homology to gp91-phox, Suh et al. (1999) identified the NOH1 gene, which they called MOX1. MOX1 was expressed in colon, prostate, uterus, and vascular smooth muscle, but not in peripheral blood leukocytes.
Kikuchi et al. (2000) cloned NOX1 and NOX3 (607105), which they termed gp91-2 and gp91-3, respectively, on the basis of sequence homology with gp91-phox. The deduced 564-amino acid NOX1 protein, which is 58% identical to CYBB, contains 6 membrane-spanning regions, conserved flavin and pyridine nucleotide-binding sites, and histidines possibly involved in heme ligation. The authors also identified a shorter isoform lacking exon 11 and, therefore, the pyridine nucleotide-binding site. Northern blot analysis revealed expression of a 2.86-kb transcript in colon but not in testis or peripheral blood leukocytes. RT-PCR analysis detected strong expression in colon, weaker expression in prostate, kidney, and testis, and faint expression in fetal brain, liver, lung, spleen, and thymus. Expression was also readily detected in liver and colon tumor cell lines. In situ hybridization analysis demonstrated clear expression in absorptive epithelial cells, but no expression in goblet cells.
In smooth muscle cells, Suh et al. (1999) found that platelet-derived growth factor (see 131222) induces MOX1 mRNA production, while antisense MOX1 mRNA decreases superoxide generation and serum-stimulated growth. Overexpression of MOX1 in NIH 3T3 cells increased superoxide generation and cell growth. Cells expressing MOX1 had a transformed appearance, showed anchorage-independent growth, and produced tumors in athymic mice. Suh et al. (1999) concluded that their data linked reactive oxygen species production by MOX1 to growth control in nonphagocytic cells.
Banfi et al. (2000) observed that the size of the 13 exons of NOX1 and CYBB is conserved, although the lengths of the introns are markedly different. Banfi et al. (2000) concluded that the presence of the 2 homologous genes is most likely due to a relatively ancient gene duplication.
Although Banfi et al. (2000) had detected 14 exons in the NOX1 gene, Banfi et al. (2005) noted in an erratum that 'exon 14' is not a separate exon but is located at the very end of exon 13.
By genomic sequence analysis, Banfi et al. (2000) localized the NOX1 gene to chromosome Xq22.
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.
Abuse of the dissociative anesthetic ketamine can lead to a syndrome indistinguishable from schizophrenia. In animals, repetitive exposure to this N-methyl-D-aspartate receptor antagonist induced the dysfunction of a subset of cortical fast-spiking inhibitory interneurons, with loss of expression of parvalbumin (168890) and the gamma-aminobutyric acid-producing enzyme GAD67 (605363). Behrens et al. (2007) showed that exposure of mice to ketamine induced a persistent increase in brain superoxide due to activation in neurons of reduced NADPH oxidase. Decreasing superoxide production prevented the effects of ketamine on inhibitory interneurons in the prefrontal cortex. Behrens et al. (2007) concluded that their results suggested that NADPH oxidase may represent a novel target for the treatment of ketamine-induced psychosis.
Voltage-gated proton (hydrogen) channels play an important role in cellular defense against acidic stress. They are unique among ion channels with respect to their extremely high selectivity, marked temperature dependence, and unitary conductance, which is 3 orders of magnitude lower than that of most other ion channels. Starace et al. (1997) demonstrated that arginine-to-histidine mutations were sufficient to turn the voltage sensor of the Shaker K+ channel (see 176260) into a voltage-gated H+ conductance. The critical residues were reminiscent of a motif within the predicted third transmembrane domain of gp91-phox, the electron-transporting subunit of the phagocyte NADPH oxidase encoded by the CYBB gene (300481).
The observation of normal H+ currents in resting phagocytes from patients deficient in gp91-phox (see 306400), and of a distinct type of H+ current activated during assembly of the NADPH oxidase, led Banfi et al. (2000) to hypothesize that, although gp91-phox may conduct proteins within an active oxidase complex, a separate protein, perhaps sharing the gp91-phox histidine motif, mediates the H+ currents of resting phagocytes and other tissues. Their search for this protein led to the identification of the NOX1 gene (see CLONING). Banfi et al. (2000) delineated 3 isoforms of the NOX1 gene, but in an erratum Banfi et al. (2005) stated that the NOH1S (or NOX1-gamma) variant was actually an artifact due to the formation of a stable loop in the NOX1 mRNA. When NOH1S was stably expressed in HEK293 cells by Banfi et al. (2000), it generated voltage-dependent, outward H+ currents. These currents were reversibly blocked by zinc, a known H+ channel inhibitor. Banfi et al. (2005) stated that although NOH1S is not a naturally occurring splice variant, the conclusion that transfection of this short form confers H+ current to cells remained valid.
Banfi, B., Maturana, A., Jaconi, S., Arnaudeau, S., Laforge, T., Sinha, S., Ligeti, E., Demaurex, N., Krause, K.-H. A mammalian H+ channel generated through alternative splicing of the NADPH oxidase homolog NOH-1. Science 287: 138-141, 2000. Note: Erratum: Science 307: 44 only, 2005. [PubMed: 10615049] [Full Text: https://doi.org/10.1126/science.287.5450.138]
Banfi, B., Maturana, A., Jaconi, S., Arnaudeau, S., Laforge, T., Sinha, S., Ligeti, E., Demaurex, N., Krause, K.-H. Corrections and clarifications: a mammalian H+ channel generated through alternative splicing of the NADPH oxidase homolog NOH-1. Science 307: 44 only, 2005.
Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., Dugan, L. L. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318: 1645-1647, 2007. [PubMed: 18063801] [Full Text: https://doi.org/10.1126/science.1148045]
Kikuchi, H., Hikage, M., Miyashita, H., Fukumoto, M. NADPH oxidase subunit, gp9l-phox homologue, preferentially expressed in human colon epithelial cells. Gene 254: 237-243, 2000. [PubMed: 10974555] [Full Text: https://doi.org/10.1016/s0378-1119(00)00258-4]
Marden, J. J., Harraz, M. M., Williams, A. J., Nelson, K., Luo, M., Paulson, H., Engelhardt, J. F. Redox modifier genes in amyotrophic lateral sclerosis in mice. J. Clin. Invest. 117: 2913-2919, 2007. [PubMed: 17853944] [Full Text: https://doi.org/10.1172/JCI31265]
Starace, D. M, Stefani, E., Bezanilla, F. Voltage-dependent proton transport by the voltage sensor of the Shaker K+ channel. Neuron 19: 1319-1327, 1997. [PubMed: 9427254] [Full Text: https://doi.org/10.1016/s0896-6273(00)80422-5]
Suh, Y.-A., Arnold, R. S., Lassegue, B., Shi, J., Xu, X., Sorescu, D., Chung, A. B., Griendling, K. K., Lambeth, J. D. Cell transformation by the superoxide-generating oxidase Mox1. Nature 401: 79-82, 1999. [PubMed: 10485709] [Full Text: https://doi.org/10.1038/43459]