Alternative titles; symbols
HGNC Approved Gene Symbol: CYBC1
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38) : 17:82,442,586-82,450,752 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Chronic granulomatous disease 5, autosomal recessive | 618935 | Autosomal recessive | 3 |
CYBC1 is a transmembrane protein that plays an essential role in innate immunity by controlling the phagocyte respiratory burst, which prevents overwhelming infection (Thomas et al., 2017).
Thomas et al. (2017) reported that mouse Cybc1, which they termed Eros, has 2 transmembrane helices in its N-terminal half and cytoplasmic N and C termini. Mouse and human EROS share approximately 89% amino acid identity. Database analysis indicated that mouse Eros is highly expressed in cells of the innate immune system, particularly neutrophils, monocytes, and macrophages. Microarray analysis of human blood subsets detected highest EROS expression in neutrophils and monocytes. Microscopic analyses of transfected mouse macrophages and HEK293T cells showed that mouse Eros localized to the endoplasmic reticulum (ER). Bioinformatic analysis identified EROS orthologs in all vertebrates, as well as in some lower-order animals, including poriferan sponges and sea urchins.
Gross (2019) mapped the CYBC1 gene to chromosome 17q25.3 based on an alignment of the CYBC1 sequence (GenBank BC004171) with the genomic sequence (GRCh38).
Thomas et al. (2017) stated that the mouse Cybc1 gene maps to chromosome 11.
By microscopic analyses of transfected mouse macrophages and HEK293T cells, Thomas et al. (2017) demonstrated that Eros colocalized in the ER with gp91phox (CYBB; 300481) and p22phox (CYBA; 608508), 2 essential membrane-bound components of cytochrome b558. Coimmunoprecipitation analysis showed that Eros interacted directly with gp91phox. Based on studies of neutrophils and macrophages from Eros -/- mice (see ANIMAL MODEL), the authors found that Eros was required for expression of gp91phox and p22phox, suggesting that Eros controls gp91phx and p22phox degradation in the ER.
Ryoden et al. (2020) found that P2X7 (P2RX7; 602566) mediated phosphatidylserine exposure in mouse and human cells in response to extracellular ATP. For this function, P2X7 required EROS to be expressed at the plasma membrane. EROS localized to the endoplasmic reticulum, where it interacted with P2X7 and assisted its folding by functioning as a chaperone. P2X7 then moved to the plasma membrane, where it was present as a homotrimeric complex. EROS was also required for P2X7-mediated production of IL1-beta (IL1B; 147720) triggered by ATP in macrophages.
In a patient, born of Saudi Arabian parents, with autosomal recessive chronic granulomatous disease-5 (CGD5; 618935), Monies et al. (2017) and Thomas et al. (2019) identified a homozygous splice site mutation in the CYBC1 gene (618334.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Western blot analysis of patient T cells showed undetectable CYBC1 protein levels, and patient neutrophils showed impaired respiratory burst activity, consistent with a functional defect in NADPH oxidase.
In 2 Icelandic brothers with CGD5, Arnadottir et al. (2018) identified a homozygous nonsense mutation in the CYBC1 gene (Y2X; 618334.0002). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Further analysis of a large Icelandic dataset identified 6 additional patients with a similar phenotype who were homozygous for Y2X. Western blot analysis of lymphocytes derived from 2 patients showed absence of the full-length protein. Functional studies showed strongly impaired PMA-induced oxidative burst in neutrophils from 1 patient. The frequency of the variant in Iceland was estimated to be 1 in 70, consistent with a founder effect.
Thomas et al. (2017) found that Eros -/- mice were highly susceptible to infection with Salmonella enterica serovar Typhimurium and Listeria monocytogenes, but not Citrobacter rodentium. Phagocyte respiratory burst was highly impaired in Eros -/- macrophages and neutrophils, and Eros -/- macrophages failed to control intracellular Salmonella replication. Eros -/- mice failed to form neutrophil extracellular traps (NETS), but were resistant to melanoma metastasis. Neutrophils and macrophages from Eros -/- mice exhibited severely reduced expression of gp91phox and p22phox.
In a patient (16W-0243), born of Saudi Arabian parents, with autosomal recessive chronic granulomatous disease-5 (CGD5; 618935), Monies et al. (2017) identified a homozygous c.127G-A transition (c.127G-A, NM_001033046) in exon 3 of the CYBC1 gene, predicted to result in an asp43-to-asn (D43N) substitution. In a follow-up report, Thomas et al. (2019) noted that the mutation was predicted to disrupt splicing. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database or in 3,300 ethnically matched exomes. Western blot analysis of patient T cells showed undetectable CYBC1 protein levels, and patient neutrophils showed impaired respiratory burst activity, consistent with a functional defect in NADPH oxidase.
In 2 Icelandic brothers with autosomal recessive chronic granulomatous disease-5 (CGD5; 618935), Arnadottir et al. (2018) identified a homozygous c.6C-G transversion (c.6C-G, NM_001033046.3) in the CYBC1 gene, resulting in a tyr2-to-ter (Y2X) substitution. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Further analysis of a large Icelandic dataset identified 6 additional patients with a similar phenotype who were homozygous for Y2X. Western blot analysis of lymphocytes derived from 2 patients showed absence of the full-length protein. Monocyte-derived macrophages from these 2 patients showed absence of the gp91phox protein (CYBB; 300481), whereas neutrophils, available from only 1 patient, showed a 50% reduction in gp91phox. Functional studies showed strongly impaired PMA-induced oxidative burst in neutrophils from 1 patient. The frequency of the variant in Iceland was estimated to be 1 in 70, consistent with a founder effect.
Arnadottir, G. A., Norddahl, G. L., Gudmundsdottir, S., Agustsdottir, A. B., Sigurdsson, S., Jensson, B. O., Bjarnadottir, K., Theodors, F., Benonisdottir, S. Ivarsdottir, E. V., Oddsson, A., Kristjansson, R. P., and 23 others. A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease. Nature Commun. 9: 4447, 2018. Note: Electronic Article. [PubMed: 30361506] [Full Text: https://doi.org/10.1038/s41467-018-06964-x]
Gross, M. B. Personal Communication. Baltimore, Md. 2/19/2019.
Monies, D., Abouelhoda, M., AlSayed, M., Alhassnan, Z., Alotaibi, M., Kayyali, H., Al-Owain, M., Shah, A., Rahbeeni, Z., Al-Muhaizea, M. A., Alzaidan, H. I., Cupler, E., and 95 others. The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum. Genet. 136: 921-939, 2017. [PubMed: 28600779] [Full Text: https://doi.org/10.1007/s00439-017-1821-8]
Ryoden, Y., Fujii, T., Segawa, K., Nagata, S. Functional expression of the P2X7 ATP receptor requires Eros. J. Immun. 204: 559-568, 2020. [PubMed: 31862710] [Full Text: https://doi.org/10.4049/jimmunol.1900448]
Thomas, D. C., Charbonnier, L.-M., Schejtman, A., Aldhekri, H., Coomber, E. L., Dufficy, E. R., Beenken, A. E., Lee,, J. C., Clare, S., Speak, A. O., Thrasher A. J., Santilli, G., Al-Mousa, H., Alkuraya, F. S., Chatila, T. A., Smith, K. G. C. EROS/CYBC1 mutations: decreased NADPH oxidase function and chronic granulomatous disease. (Letter) J. Allergy Clin. Immun. 143: 782-785, 2019. [PubMed: 30312704] [Full Text: https://doi.org/10.1016/j.jaci.2018.09.019]
Thomas, D. C., Clare, S., Sowerby, J. M., Pardo, M., Juss, J. K., Goulding, D. A., van der Weyden, L., Storisteanu, D., Prakash, A., Espeli, M., Flint, S., Lee, J. C., and 15 others. Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity. J. Exp. Med. 214: 1111-1128, 2017. [PubMed: 28351984] [Full Text: https://doi.org/10.1084/jem.20161382]