Alternative titles; symbols
HGNC Approved Gene Symbol: CYBB
Cytogenetic location: Xp21.1-p11.4 Genomic coordinates (GRCh38) : X:37,780,059-37,813,461 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp21.1-p11.4 | Chronic granulomatous disease, X-linked | 306400 | X-linked recessive | 3 |
| Immunodeficiency 34, mycobacteriosis, X-linked | 300645 | X-linked recessive | 3 |
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 (see NOX1, 300225), 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 (NCF1; 608512), p67-phox (233710), p40-phox (NCF4; 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).
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 composed 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.
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.
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.
By positional cloning, Royer-Pokora et al. (1986) identified the CYBB gene at Xp21.
Gross (2014) mapped the CYBB gene to chromosome Xp11.4 based on an alignment of the CYBB sequence (GenBank AF469769) with the genomic sequence (GRCh38).
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.
Chronic Granulomatous Disease, X-linked
In a male patient with the cytochrome b-positive variant of X-linked CGD (CGDX; 306400), Dinauer et al. (1989) identified a hemizygous missense mutation in the CYBB gene (P415H; 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.
Immunodeficiency 34
In 7 males from 2 kindreds with X-linked familial atypical mycobacteriosis (IMD34; 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 bacillus Calmette-Guerin (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.
Enhanced redox stress and inflammation are associated with progression of amyotrophic lateral sclerosis (ALS; 105400). Marden et al. (2007) evaluated the effects of Nox1 (300225) 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.
Deffert et al. (2014) conducted a literature search that found nearly 300 cases of mycobacterial infection in CGD, principally caused by M. bovis BCG. The authors then investigated BCG infection in 3 different mouse models of CGD: 2 strains of mice lacking Ncf1 and mice lacking Cybb. All 3 CGD mouse strains were highly susceptible to intravenous BCG infection, manifest as severe weight loss, hemorrhagic pneumonia with high numbers of neutrophils, and 50% mortality. These mice had only moderately increased bacterial load. Macrophage-specific rescue of Cybb restored BCG resistance. ROS was generated in granulomas of wildtype mice, but not CGD mice. Massive increases in the release of the cytokines Tnf (191160), Ifng (147570), Il17 (603149), and Il12 (161561), as well as Cxcl1 (155730), a neutrophil chemoattractant, occurred early after infection in CGD mice, possibly explaining disease severity. Macrophages clustered in granulomas in wildtype mice, whereas macrophages were diffusely distributed in lungs of CGD mice. Deffert et al. (2014) concluded that lack of NADPH oxidase leads to markedly increased severity of BCG infection through increased cytokine production and reduced granuloma formation.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
See 300481.0016, Stasia et al. (2002), and Bionda et al. (2004).
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.
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.
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.
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.
In 4 maternally related French males with X-linked familial atypical mycobacteriosis (IMD34; 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.
In 3 maternally related French males with X-linked familial atypical mycobacteriosis (IMD34; 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.
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