* 164910

REL PROTOONCOGENE, NF-KAPPA-B SUBUNIT; REL


Alternative titles; symbols

V-REL AVIAN RETICULOENDOTHELIOSIS VIRAL ONCOGENE HOMOLOG
ONCOGENE REL
C-REL


HGNC Approved Gene Symbol: REL

Cytogenetic location: 2p16.1     Genomic coordinates (GRCh38): 2:60,881,574-60,931,612 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2p16.1 Immunodeficiency 92 619652 AR 3

TEXT

Description

The REL gene encodes c-Rel, a transcription factor that is a member of the Rel/NFKB family, which also includes RELA (164014), RELB (604758), NFKB1 (164011), and NFKB2 (164012). These proteins are related through a highly conserved N-terminal region termed the 'Rel domain,' which is responsible for DNA binding, dimerization, nuclear localization, and binding to the NFKB inhibitor (164008) (Belguise and Sonenshein, 2007).

REL is critical for T- and B-cell function in the immune system, as it binds to the promoters of genes that encode cytokines important for immunity against infectious pathogens, including IL2 (147680), IFNG (147570), IL12 (see 161560), and IL23 (see 605580) (summary by Beaussant-Cohen et al., 2019).


Cloning and Expression

Brownell et al. (1985) isolated a partial genomic segment corresponding to the REL gene. Subsequently, Brownell et al. (1989) cloned full-length REL from a human Daudi cell cDNA library.

Levy et al. (2021) found strong expression of the REL gene in EBV-B cells and in all leukocyte subsets studied, with the highest levels being in gamma/delta T cells, naive CD19+ B cells, CD16+ monocytes, and conventional dendritic cells (DC1).


Mapping

By in situ hybridization, Brownell et al. (1986) assigned the REL locus to 2p13-2cen. They assigned mouse Rel gene chromosome 11, which has shown no homology to human chromosome 2, and to feline chromosome A3, which does show homology to human 2p.

By translocation chromosome analysis, Brownell et al. (1988) mapped the REL gene to chromosome 2p13-p12.

Stumpf (2020) mapped the REL gene to chromosome 2p16.1 based on an alignment of the REL sequence (GenBank BC143885) with the genomic sequence (GRCh38).


Gene Function

Romieu-Mourez et al. (2003) noted that amplification, overexpression, or rearrangement of the c-rel gene has been detected in solid and hematologic malignancies, including breast cancer (114480).

Belguise and Sonenshein (2007) identified the estrogen receptor-alpha (ESR1; 133430) as a potent inhibitor of c-Rel DNA binding in murine mammary gland tissue and tumors. Further studies identified protein kinase C-theta (PRKCQ; 600448) as a positive regulator of c-Rel transcriptional activity, as well as downstream target genes. In human breast cancer cell lines, there was an inverse correlation between ESR1 and PRKCQ mRNA, and PRKCQ was found to inhibit ESR1 expression via activation of AKT1 (164730). Belguise and Sonenshein (2007) concluded that PRKCQ plays a pivotal role in mammary tumorigenesis by activating AKT, which ultimately leads to derepression of c-Rel through inhibition of ESR1.


Molecular Genetics

Immunodeficiency 92

In a 9-year-old boy, born of consanguineous Arab parents, with immunodeficiency-92 (IMD92; 619652), Beaussant-Cohen et al. (2019) identified a homozygous splice site mutation in the REL gene (164910.0001), resulting in complete REL deficiency with absent protein expression. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was absent from the gnomAD database. Patient T cells showed impaired proliferative responses to PHA stimulation and undetectable IFNG production; B cells also showed poor proliferation and defects in humoral immunity. There was poor secretion of IL12 (see 161560), IL21 (605384), and IL23 (see 605580) by antigen-presenting cells. The findings were consistent with a combined immunodeficiency.

In a girl, born of consanguineous Moroccan parents, with IMD92, Levy et al. (2021) identified a homozygous splice site mutation in the REL gene (164910.0002), resulting in a complete loss of function. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Analysis of patient lymphocytes showed that REL deficiency altered the development of certain subsets, including NK cells, certain CD4+ and CD8+ T cells, T helper cells, Treg cells, and memory B cells.

Associations Pending Confirmation

For discussion of a possible association between variation in the REL gene and susceptibility to rheumatoid arthritis, see 180300.


Animal Model

Romieu-Mourez et al. (2003) developed a mouse model in which the mouse c-rel gene was driven by a hormone-dependent mouse mammary tumor virus promoter (MMTV). Approximately 32% of female transgenic mice developed late-onset mammary tumors at an average age of 19.9 months. Mammary tumors were of diverse histology and expressed increased levels of nuclear Nfkb. There was also increased expression of cancer-related Nfkb target genes, including cyclin D1 (CCND1; 168461) and c-myc (190080). The findings indicated that dysregulated expression of c-rel is capable of contributing to mammary tumorigenesis.

Gugasyan et al. (2004) demonstrated that c-rel is expressed in the epidermis and hair follicles of normal mouse embryos. Mutant mice lacking both c-rel and RelA displayed multiple epidermal defects, including thin epidermis and failure to form tylotrich hair. Although mutant keratinocytes underwent terminal differentiation, mutant basal keratinocytes were abnormally small, showed growth delay, and failed to form colonies in culture. The findings indicated that c-rel and RelA regulate skin development in a redundant manner and that both are required for normal epidermal development in mice.


ALLELIC VARIANTS ( 2 Selected Examples):

.0001 IMMUNODEFICIENCY 92

REL, IVS5DS, G-A, +1
  
RCV001794567

In a 9-year-old boy, born of consanguineous Arab parents, with immunodeficiency-92 (IMD92; 619652), Beaussant-Cohen et al. (2019) identified a homozygous G-to-A transition (c.535+1G-A, NM_002908.3) in intron 5 of the REL gene, resulting in a splice site mutation and altered splicing that was demonstrated in patient cells. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was absent from the gnomAD database. Patient cells showed absence of the REL protein, consistent with complete REL deficiency.


.0002 IMMUNODEFICIENCY 92

REL, IVS5AS, G-A, -1
  
RCV001794568

In a girl, born of consanguineous Moroccan parents, with immunodeficiency-92 (IMD92; 619652), Levy et al. (2021) identified a homozygous G-to-A transition (c.395-1G-A) in intron 5 of the REL gene, predicted to result in a splicing defect, a frameshift, and premature termination. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Further studies showed that the mutation resulted in nonsense-mediated mRNA decay and absence of the REL protein, consistent with a loss of function.


REFERENCES

  1. Beaussant-Cohen, S., Jaber, F., Massaad, M. J., Weeks, S., Jones, J., Alosaimi, M. F., Wallace, J., Al-Herz, W., Geha, R. S., Chou, J. Combined immunodeficiency in a patient with c-Rel deficiency. J. Allergy Clin. Immun. 144: 606-608, 2019. [PubMed: 31103457, images, related citations] [Full Text]

  2. Belguise, K., Sonenshein, G. E. PKC-theta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor-alpha synthesis. J. Clin. Invest. 117: 4009-4021, 2007. [PubMed: 18037997, images, related citations] [Full Text]

  3. Brownell, E., Fell, H. P., Tucker, P. W., Geurts van Kessel, A. H., Hagemeijer, A., Rice, N. R. Regional localization of the human c-rel locus using translocation chromosome analysis. Oncogene 2: 527-529, 1988. [PubMed: 3287280, related citations]

  4. Brownell, E., Kozak, C. A., Fowle, J. R., III, Modi, W. S., Rice, N. R., O'Brien, S. J. Comparative genetic mapping of cellular rel sequences in man, mouse and the domestic cat. Am. J. Hum. Genet. 39: 194-202, 1986. [PubMed: 3529946, related citations]

  5. Brownell, E., Mittereder, N., Rice, N. R. A human rel proto-oncogene cDNA containing an Alu fragment as a potential coding exon. Oncogene 4: 935-942, 1989. [PubMed: 2666912, related citations]

  6. Brownell, E., O'Brien, S. J., Nash, W. G., Rice, N. Genetic characterization of human c-rel sequences. Molec. Cell. Biol. 5: 2826-2831, 1985. [PubMed: 3016517, related citations] [Full Text]

  7. Gugasyan, R., Voss, A., Varigos, G., Thomas, T., Grumont, R. J., Kaur, P., Grigoriadis, G., Gerondakis, S. The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms. Molec. Cell. Biol. 24: 5733-5745, 2004. [PubMed: 15199130, images, related citations] [Full Text]

  8. Levy, R., Langlais, D., Beziat, V., Rapaport, F., Rao, G., Lazarov, T., Bourgey, M., Zhou, Y. J., Briand, C., Moriya, K., Ailal, F., Avery, D. T., and 35 others. Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents. J. Clin. Invest. 131: e150143, 2021. [PubMed: 34623332, images, related citations] [Full Text]

  9. Romieu-Mourez, R., Kim, D. W., Shin, S. M., Demicco, E. G., Landesman-Bollag, E., Seldin, D. C., Cardiff, R. D., Sonenshein, G. E. Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors. Molec. Cell. Biol. 23: 5738-5754, 2003. [PubMed: 12897145, images, related citations] [Full Text]

  10. Stumpf, A. M. Personal Communication. Baltimore, Md. 07/31/2020.


Cassandra L. Kniffin - updated : 12/08/2021
Anne M. Stumpf - updated : 07/31/2020
Cassandra L. Kniffin - updated : 3/13/2008
Creation Date:
Victor A. McKusick : 6/2/1986
alopez : 12/13/2021
ckniffin : 12/08/2021
alopez : 07/31/2020
carol : 07/30/2020
wwang : 08/18/2009
ckniffin : 8/6/2009
wwang : 5/16/2008
ckniffin : 3/13/2008
mark : 6/10/1996
carol : 4/27/1993
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989
marie : 3/25/1988
carol : 2/29/1988

* 164910

REL PROTOONCOGENE, NF-KAPPA-B SUBUNIT; REL


Alternative titles; symbols

V-REL AVIAN RETICULOENDOTHELIOSIS VIRAL ONCOGENE HOMOLOG
ONCOGENE REL
C-REL


HGNC Approved Gene Symbol: REL

Cytogenetic location: 2p16.1     Genomic coordinates (GRCh38): 2:60,881,574-60,931,612 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2p16.1 Immunodeficiency 92 619652 Autosomal recessive 3

TEXT

Description

The REL gene encodes c-Rel, a transcription factor that is a member of the Rel/NFKB family, which also includes RELA (164014), RELB (604758), NFKB1 (164011), and NFKB2 (164012). These proteins are related through a highly conserved N-terminal region termed the 'Rel domain,' which is responsible for DNA binding, dimerization, nuclear localization, and binding to the NFKB inhibitor (164008) (Belguise and Sonenshein, 2007).

REL is critical for T- and B-cell function in the immune system, as it binds to the promoters of genes that encode cytokines important for immunity against infectious pathogens, including IL2 (147680), IFNG (147570), IL12 (see 161560), and IL23 (see 605580) (summary by Beaussant-Cohen et al., 2019).


Cloning and Expression

Brownell et al. (1985) isolated a partial genomic segment corresponding to the REL gene. Subsequently, Brownell et al. (1989) cloned full-length REL from a human Daudi cell cDNA library.

Levy et al. (2021) found strong expression of the REL gene in EBV-B cells and in all leukocyte subsets studied, with the highest levels being in gamma/delta T cells, naive CD19+ B cells, CD16+ monocytes, and conventional dendritic cells (DC1).


Mapping

By in situ hybridization, Brownell et al. (1986) assigned the REL locus to 2p13-2cen. They assigned mouse Rel gene chromosome 11, which has shown no homology to human chromosome 2, and to feline chromosome A3, which does show homology to human 2p.

By translocation chromosome analysis, Brownell et al. (1988) mapped the REL gene to chromosome 2p13-p12.

Stumpf (2020) mapped the REL gene to chromosome 2p16.1 based on an alignment of the REL sequence (GenBank BC143885) with the genomic sequence (GRCh38).


Gene Function

Romieu-Mourez et al. (2003) noted that amplification, overexpression, or rearrangement of the c-rel gene has been detected in solid and hematologic malignancies, including breast cancer (114480).

Belguise and Sonenshein (2007) identified the estrogen receptor-alpha (ESR1; 133430) as a potent inhibitor of c-Rel DNA binding in murine mammary gland tissue and tumors. Further studies identified protein kinase C-theta (PRKCQ; 600448) as a positive regulator of c-Rel transcriptional activity, as well as downstream target genes. In human breast cancer cell lines, there was an inverse correlation between ESR1 and PRKCQ mRNA, and PRKCQ was found to inhibit ESR1 expression via activation of AKT1 (164730). Belguise and Sonenshein (2007) concluded that PRKCQ plays a pivotal role in mammary tumorigenesis by activating AKT, which ultimately leads to derepression of c-Rel through inhibition of ESR1.


Molecular Genetics

Immunodeficiency 92

In a 9-year-old boy, born of consanguineous Arab parents, with immunodeficiency-92 (IMD92; 619652), Beaussant-Cohen et al. (2019) identified a homozygous splice site mutation in the REL gene (164910.0001), resulting in complete REL deficiency with absent protein expression. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was absent from the gnomAD database. Patient T cells showed impaired proliferative responses to PHA stimulation and undetectable IFNG production; B cells also showed poor proliferation and defects in humoral immunity. There was poor secretion of IL12 (see 161560), IL21 (605384), and IL23 (see 605580) by antigen-presenting cells. The findings were consistent with a combined immunodeficiency.

In a girl, born of consanguineous Moroccan parents, with IMD92, Levy et al. (2021) identified a homozygous splice site mutation in the REL gene (164910.0002), resulting in a complete loss of function. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Analysis of patient lymphocytes showed that REL deficiency altered the development of certain subsets, including NK cells, certain CD4+ and CD8+ T cells, T helper cells, Treg cells, and memory B cells.

Associations Pending Confirmation

For discussion of a possible association between variation in the REL gene and susceptibility to rheumatoid arthritis, see 180300.


Animal Model

Romieu-Mourez et al. (2003) developed a mouse model in which the mouse c-rel gene was driven by a hormone-dependent mouse mammary tumor virus promoter (MMTV). Approximately 32% of female transgenic mice developed late-onset mammary tumors at an average age of 19.9 months. Mammary tumors were of diverse histology and expressed increased levels of nuclear Nfkb. There was also increased expression of cancer-related Nfkb target genes, including cyclin D1 (CCND1; 168461) and c-myc (190080). The findings indicated that dysregulated expression of c-rel is capable of contributing to mammary tumorigenesis.

Gugasyan et al. (2004) demonstrated that c-rel is expressed in the epidermis and hair follicles of normal mouse embryos. Mutant mice lacking both c-rel and RelA displayed multiple epidermal defects, including thin epidermis and failure to form tylotrich hair. Although mutant keratinocytes underwent terminal differentiation, mutant basal keratinocytes were abnormally small, showed growth delay, and failed to form colonies in culture. The findings indicated that c-rel and RelA regulate skin development in a redundant manner and that both are required for normal epidermal development in mice.


ALLELIC VARIANTS 2 Selected Examples):

.0001   IMMUNODEFICIENCY 92

REL, IVS5DS, G-A, +1
SNP: rs2103978347, ClinVar: RCV001794567

In a 9-year-old boy, born of consanguineous Arab parents, with immunodeficiency-92 (IMD92; 619652), Beaussant-Cohen et al. (2019) identified a homozygous G-to-A transition (c.535+1G-A, NM_002908.3) in intron 5 of the REL gene, resulting in a splice site mutation and altered splicing that was demonstrated in patient cells. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was absent from the gnomAD database. Patient cells showed absence of the REL protein, consistent with complete REL deficiency.


.0002   IMMUNODEFICIENCY 92

REL, IVS5AS, G-A, -1
SNP: rs2103978009, ClinVar: RCV001794568

In a girl, born of consanguineous Moroccan parents, with immunodeficiency-92 (IMD92; 619652), Levy et al. (2021) identified a homozygous G-to-A transition (c.395-1G-A) in intron 5 of the REL gene, predicted to result in a splicing defect, a frameshift, and premature termination. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Further studies showed that the mutation resulted in nonsense-mediated mRNA decay and absence of the REL protein, consistent with a loss of function.


REFERENCES

  1. Beaussant-Cohen, S., Jaber, F., Massaad, M. J., Weeks, S., Jones, J., Alosaimi, M. F., Wallace, J., Al-Herz, W., Geha, R. S., Chou, J. Combined immunodeficiency in a patient with c-Rel deficiency. J. Allergy Clin. Immun. 144: 606-608, 2019. [PubMed: 31103457] [Full Text: https://doi.org/10.1016/j.jaci.2019.05.003]

  2. Belguise, K., Sonenshein, G. E. PKC-theta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor-alpha synthesis. J. Clin. Invest. 117: 4009-4021, 2007. [PubMed: 18037997] [Full Text: https://doi.org/10.1172/JCI32424]

  3. Brownell, E., Fell, H. P., Tucker, P. W., Geurts van Kessel, A. H., Hagemeijer, A., Rice, N. R. Regional localization of the human c-rel locus using translocation chromosome analysis. Oncogene 2: 527-529, 1988. [PubMed: 3287280]

  4. Brownell, E., Kozak, C. A., Fowle, J. R., III, Modi, W. S., Rice, N. R., O'Brien, S. J. Comparative genetic mapping of cellular rel sequences in man, mouse and the domestic cat. Am. J. Hum. Genet. 39: 194-202, 1986. [PubMed: 3529946]

  5. Brownell, E., Mittereder, N., Rice, N. R. A human rel proto-oncogene cDNA containing an Alu fragment as a potential coding exon. Oncogene 4: 935-942, 1989. [PubMed: 2666912]

  6. Brownell, E., O'Brien, S. J., Nash, W. G., Rice, N. Genetic characterization of human c-rel sequences. Molec. Cell. Biol. 5: 2826-2831, 1985. [PubMed: 3016517] [Full Text: https://doi.org/10.1128/mcb.5.10.2826-2831.1985]

  7. Gugasyan, R., Voss, A., Varigos, G., Thomas, T., Grumont, R. J., Kaur, P., Grigoriadis, G., Gerondakis, S. The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms. Molec. Cell. Biol. 24: 5733-5745, 2004. [PubMed: 15199130] [Full Text: https://doi.org/10.1128/MCB.24.13.5733-5745.2004]

  8. Levy, R., Langlais, D., Beziat, V., Rapaport, F., Rao, G., Lazarov, T., Bourgey, M., Zhou, Y. J., Briand, C., Moriya, K., Ailal, F., Avery, D. T., and 35 others. Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents. J. Clin. Invest. 131: e150143, 2021. [PubMed: 34623332] [Full Text: https://doi.org/10.1172/JCI150143]

  9. Romieu-Mourez, R., Kim, D. W., Shin, S. M., Demicco, E. G., Landesman-Bollag, E., Seldin, D. C., Cardiff, R. D., Sonenshein, G. E. Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors. Molec. Cell. Biol. 23: 5738-5754, 2003. [PubMed: 12897145] [Full Text: https://doi.org/10.1128/MCB.23.16.5738-5754.2003]

  10. Stumpf, A. M. Personal Communication. Baltimore, Md. 07/31/2020.


Contributors:
Cassandra L. Kniffin - updated : 12/08/2021
Anne M. Stumpf - updated : 07/31/2020
Cassandra L. Kniffin - updated : 3/13/2008

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
alopez : 12/13/2021
ckniffin : 12/08/2021
alopez : 07/31/2020
carol : 07/30/2020
wwang : 08/18/2009
ckniffin : 8/6/2009
wwang : 5/16/2008
ckniffin : 3/13/2008
mark : 6/10/1996
carol : 4/27/1993
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989
marie : 3/25/1988
carol : 2/29/1988