Alternative titles; symbols
HGNC Approved Gene Symbol: NCF2
Cytogenetic location: 1q25.3 Genomic coordinates (GRCh38) : 1:183,555,562-183,601,849 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q25.3 | Chronic granulomatous disease 2, autosomal recessive | 233710 | Autosomal recessive | 3 |
Neutrophil cytosolic factor-2 (NCF2), also known as p67-phox (for phagocyte oxidase), is a component of the NADPH oxidase complex.
Leto et al. (1990) cloned a p67-phox cDNA that encodes a 526-amino acid protein with a molecular mass of 67 kD. The protein has acidic middle and C-terminal domains that are similar to a sequence motif found in the noncatalytic domain of src (190090)-related tyrosine kinases. Kenney et al. (1993) cloned and characterized the NCF2 gene.
Kenney et al. (1993) determined that the NCF2 gene has 16 exons spanning 40 kb.
By Southern blot analysis of DNA from human/rodent somatic cell hybrids, Hsieh et al. (1989) demonstrated that the human NCF2 gene is located in the region 1cen-q32.
By Southern blot analysis of somatic cell hybrid lines and chromosomal in situ hybridization, Francke et al. (1990) localized NCF2 to 1q25. In the mouse, the corresponding locus Ncf2 was mapped with somatic cell hybrid panels and recombinant inbred strains to chromosome 1 near the locus for endogenous xenotropic virus-21 (Xmv-21) in an area known to be homologous to human chromosome region 1q21-q32.
Using neutrophils from a patient with p67-deficient CGD, Okamura et al. (1990) confirmed that the p67 protein functions in the respiratory burst mediated by NADPH oxidase and that p67 may be complexed to p47-phox (NCF1; 608512) while it participates in oxidase activation.
In patients with autosomal recessive chronic granulomatous disease-2 (CGD2; 233710), Nunoi et al. (1995) and Bonizzato et al. (1997) identified mutations in the NCF2 gene (see, e.g., 608515.0001).
Patino et al. (1999) reported the biochemical and molecular characterization of 6 unrelated individuals with p67-phox deficiency. They found, as in CGD of other causes, extensive allelic heterogeneity. Five different mutant alleles were identified (see, e.g., 608515.0003-608515.0006).
Noack et al. (1999) studied 6 patients from 5 families with p67-phox deficiency and identified 7 different mutant alleles (see, e.g., 608515.0007-608515.0009). Patients from 3 of the kindreds were homozygous for their respective mutation, although the parents of only 1 family were known to be related. Five of the mutations had not previously been identified. Noack et al. (1999) stated that prior to their study, 12 mutations in the NCF2 gene had been documented (de Boer et al., 1994; Tanugi-Cholley et al., 1995; Nunoi et al., 1995; Aoshima et al., 1996; Patino et al., 1999).
Sancho-Shimizu and Malo (2006) evaluated Ncf2 as a candidate for Ity3, a quantitative trait locus for recessive susceptibility to Salmonella Typhimuriu infection on distal mouse chromosome 1. They identified a G-to-A transition at nucleotide 1181 in Ncf2 that resulted in a nonconservative arg394-to-gln (R394Q) substitution. Real-time PCR detected significantly reduced Ncf2 expression in susceptible mice after Salmonella infection. Macrophages from susceptible mice produced lower levels of superoxide in response to Ifng (147570), mitogen, or infection. Sancho-Shimizu and Malo (2006) noted that R394Q corresponds to a human mutation, arg395 to trp (R395W; 608515.0010), identified in patients with CGD that results in significantly impaired NADPH oxidase activity and reduced heterodimerization of NCF2 with NCF4 (601488).
In a Japanese patient with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), Nunoi et al. (1995) identified a 399AG insertion in the NCF2 gene. The patient was homozygous for the insertion, while his parents were heterozygous. The AG insertion was predicted to induce a frameshift and produce a stop codon at position 433. Neutrophils from the patient completely lacked superoxide generating activity, whereas those from his parents generated substantial amounts of superoxide anion upon stimulation.
In the neutrophils of a patient with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), Bonizzato et al. (1997) found that the NCF2 mRNA was present in normal amount and size. Reverse transcription SSCP analysis followed by direct DNA sequencing identified a heterozygous double substitution: a 479A-T transversion, resulting in a lys160 to glu (K160E) substitution, and a 481A-G transition, resulting in an asp161 to val (D161V) substitution, both in exon 5 of the NCF2 gene. This was a double nonconservative amino acid change. The nature of the mutation on the other allele was not identified.
In an 8-year-old Hispanic girl with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), the offspring of unrelated parents, Patino et al. (1999) identified a homozygous 304C-T transition in exon 4 of the NCF2 gene. Each of the parents was heterozygous. The mutation predicted the replacement of arg102 with a TGA stop codon. The diagnosis of CGD had been made at age 8 months when the patient presented with a right upper lobe pneumonia caused by Serratia marcescens.
In a 10-year-old girl with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), the offspring of first-cousin parents native to Jordan, Patino et al. (1999) identified a homozygous deletion of 5 nucleotides, 1169-1173, at the 3-prime end of exon 13 of the NCF2 gene. The patient's parents were heterozygous for the mutation. Her sister, aged 2 years, also showed the genetic defect but had not yet developed serious illness or required hospitalization.
Patino et al. (1999) found the same mutation in an unrelated affected Palestinian patient. This patient was also homozygous for the deletion, and the first-cousin parents were heterozygous and of Palestinian descent.
In a girl with p67-phox-deficient chronic granulomatous disease (CGD2; 233710) who died at age 4 years, Patino et al. (1999) found homozygosity for a G-to-A transition in the first nucleotide in the consensus splice site of intron 4. The mutation led to the production of 3 different species of cDNA: one that lacked exons 3 and 4, a second with a deletion of exon 4, and a third that lacked only the last 5 nucleotides of exon 4. The different skipping was the result of alternative splicing, including the use of a cryptic splice site. The girl was homozygous, although the parents were thought to be nonconsanguineous; they were natives of a small town in Mexico.
In a 16-year-old girl with chronic granulomatous disease (CGD2; 233710), the offspring of unrelated parents who were natives of Mexico, Patino et al. (1999) found compound heterozygosity for a 9-bp deletion (AAGAAGGAC) involving nucleotides 55-63 in exon 2 of the NCF2 gene, predicting elimination of lys19/lys20/asp21 from the NCF2 protein. The maternal allele also contained a C-to-T transition at nucleotide 1183 in exon 14, resulting in an arg395-to-trp mutation (R395W; 608515.0010). The mother was heterozygous for these mutations. The allele from the father had an IVS4DS+1G-A mutation (608515.0005).
In a family with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), Noack et al. (1999) identified a 383C-T transition in exon 5 of the NCF2 gene, resulting in an ala128-to-val (A128V) amino acid substitution. The mutation was present in homozygous state in 2 affected sibs.
In a family with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), Noack et al. (1999) identified compound heterozygosity for 2 mutations in the NCF2 gene: a 230G-A transition, resulting in an arg77-to-gln (R77Q) substitution inherited from the mother, and a nonsense mutation, 298C-T, which changed codon 100 from CAG (gln) to TAG (stop) (Q100X; 608515.0009) in the allele inherited from the father.
For discussion of the gln100-to-ter (Q100X) mutation in the NCF2 gene that was found in compound heterozygous state in a family with p67-phox-deficient chronic granulomatous disease (CGD2; 233710) by Noack et al. (1999), see 608515.0008.
In a 16-year-old girl with p67-phox-deficient chronic granulomatous disease (CGD2; 233710), the offspring of unrelated parents who were natives of Mexico, Patino et al. (1999) found compound heterozygosity for mutations in the NCF2 gene. The maternal allele contained an in-frame deletion of 9 nucleotides in the middle of exon 2 (608515.0006) and a C-to-T transition at nucleotide 1183 in exon 14, resulting in an arg395-to-trp mutation (R395W). The paternal allele had an IVS4DS+1G-A mutation (608515.0005). Recombinant NCF2 protein carrying only the R395W mutation supported superoxide production in a cell-free NADPH oxidase activation system at a level approximately 15% of normal.
Aoshima, M., Nunoi, H., Shimazu, M., Shimizu, S., Tatsuzawa, O., Kenney, R. T., Kanegasaki, S. Two-exon skipping due to a point mutation in p67-phox-deficient chronic granulomatous disease. Blood 88: 1841-1845, 1996. [PubMed: 8781442]
Bonizzato, A., Russo, M. P., Donini, M., Dusi, S. Identification of a double mutation (D160V-K161E) (sic) in the p67phox gene of a chronic granulomatous disease patient. Biochem. Biophys. Res. Commun. 231: 861-863, 1997. [PubMed: 9070911] [Full Text: https://doi.org/10.1006/bbrc.1997.6204]
de Boer, M., Hilarius-Stokman, P. M., Hossle, J.-P., Verhoeven, A. J., Graf, N., Kenney, R. T., Seger, R., Roos, D. Autosomal recessive chronic granulomatous disease with absence of the 67-kD cytosolic NADPH oxidase component: identification of mutation and detection of carriers. Blood 83: 531-536, 1994. [PubMed: 8286749]
Francke, U., Hsieh, C.-L., Foellmer, B. E., Lomax, K. J., Malech, H. L., Leto, T. L. Genes for two autosomal recessive forms of chronic granulomatous disease assigned to 1q25 (NCF2) and 7q11.23 (NCF1). Am. J. Hum. Genet. 47: 483-492, 1990. [PubMed: 2393022]
Hsieh, C. L., Leto, T. L., Lomax, K. J., Malech, H. L., Francke, U. The genes for two neutrophil cytosol factors that are deficient in autosomal forms of chronic granulomatous disease are on human chromosome 10 (47 kD), and chromosome 1 cen-q32 (65 kD). (Abstract) Cytogenet. Cell Genet. 51: 1015-1016, 1989.
Kenney, R. T., Malech, H. L., Epstein, N. D., Roberts, R. L., Leto, T. L. Characterization of the p67-phox gene: genomic organization and restriction fragment length polymorphism analysis for prenatal diagnosis in chronic granulomatous disease. Blood 82: 3739-3744, 1993. [PubMed: 7903171]
Leto, T. L., Lomax, K. J., Volpp, B. D., Nunoi, H., Sechler, J. M. G., Nauseef, W. M., Clark, R. A., Gallin, J. I., Malech, H. L. Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src. Science 248: 727-730, 1990. [PubMed: 1692159] [Full Text: https://doi.org/10.1126/science.1692159]
Noack, D., Rae, J., Cross, A. R., Munoz, J., Salmen, S., Mendoza, J. A., Rossi, N., Curnutte, J. T., Heyworth, P. G. Autosomal recessive chronic granulomatous disease caused by novel mutations in NCF-2, the gene encoding the p67-phox component of phagocyte NADPH oxidase. Hum. Genet. 105: 460-467, 1999. [PubMed: 10598813] [Full Text: https://doi.org/10.1007/s004390051131]
Nunoi, H., Iwata, M., Tatsuzawa, S., Onoe, Y., Shimizu, S., Kanegasaki, S., Matsuda, I. AG dinucleotide insertion in a patient with chronic granulomatous disease lacking cytosolic 67-kD protein. Blood 86: 329-333, 1995. [PubMed: 7795241]
Okamura, N., Babior, B. M., Mayo, L. A., Peveri, P., Smith, R. M., Curnutte, J. T. The p67-phox cytosolic peptide of the respiratory burst oxidase from human neutrophils: functional aspects. J. Clin. Invest. 85: 1583-1587, 1990. [PubMed: 2159023] [Full Text: https://doi.org/10.1172/JCI114608]
Patino, P. J., Rae, J., Noack, D., Erickson, R., Ding, J., Garcia de Olarte, D., Curnutte, J. T. Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox. Blood 94: 2505-2514, 1999. [PubMed: 10498624]
Sancho-Shimizu, V., Malo, D. Sequencing, expression, and functional analyses support the candidacy of Ncf2 in susceptibility to Salmonella Typhimurium infection in wild-derived mice. J. Immun. 176: 6954-6961, 2006. [PubMed: 16709856] [Full Text: https://doi.org/10.4049/jimmunol.176.11.6954]
Tanugi-Cholley, L. C., Issartel, J.-P., Lunardi, J., Freycon, F., Morel, F., Vignais, P. V. A mutation located at the 5-prime splice junction sequence of intron 3 in the p67-phox gene causes the lack of p67-phox mRNA in a patient with chronic granulomatous disease. Blood 85: 242-249, 1995. [PubMed: 7803798]