Alternative titles; symbols
HGNC Approved Gene Symbol: CD3G
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:118,344,344-118,355,161 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Immunodeficiency 17, CD3 gamma deficient | 615607 | Autosomal recessive | 3 |
The alpha-beta heterodimeric T-cell antigen receptor (TCR) binds antigen in association with major histocompatibility complex proteins on host cell surfaces. These 2 disulfide-linked glycoproteins, TCRA (see 186880) and TCRB (see 186930), are associated on T-cell surfaces with a complex of proteins called CD3 (formerly T3). Human CD3 consists of at least 4 proteins: gamma, delta (186790), epsilon (CD3E; 186830), and zeta (186780).
Krissansen et al. (1986) found striking homology between the gamma and delta subunits.
Tunnacliffe et al. (1987) determined that the CD3-gamma gene contains 7 exons spanning over 9 kb of genomic DNA.
Using standard cloning techniques, together with field inversion gel electrophoresis, Tunnacliffe et al. (1987) demonstrated the close physical linkage of 3 CD3 genes. The genes for CD3-gamma and CD3-delta are situated close together, about 1.6 kb apart, organized in a head-to-head orientation. The CD3-gamma/CD3-delta gene pair is within 300 kb of the CD3-epsilon gene and therefore these genes form a tightly linked cluster on 11q23. The clustering may be significant in terms of their simultaneous activations during T-cell development. The separation of CD3E from CD3G/CD3D may be as little as 20 kb. By field inversion gel electrophoresis and molecular cloning, Tunnacliffe et al. (1988) found that the 3 genes lie within a stretch of 50 kb of DNA, oriented 3-prime--CD3G--5-prime:5-prime--CD3D--3-prime:3-prime--CD3E--5-prime.
Saito et al. (1987) also reported close physical linkage of the human CD3G and CD3D genes; in addition, they found that this is also true in the mouse. This suggested coordinate expression of the 2 genes during intrathymic maturation of T lymphocytes. The homologous mouse genes are on chromosome 9. Saito et al. (1987) presented data that the CD3G gene is located 1.4 kb from CD3D, and within about 400 kb of the CD3E gene. The CD3G and CD3D genes are divergently transcribed, an unusual finding. Regulatory elements may exist in the area between the transcription initiation sites.
Krissansen et al. (1987) localized CD3G to 11q23 by means of Southern blot analysis of a panel of somatic cell hybrid DNAs and by in situ hybridization.
Evans et al. (1988) demonstrated by restriction mapping that all 3 CD3 subunits are encoded within 60 kb of DNA, with the CD3-epsilon gene located 26 kb downstream of the CD3-delta and CD3-gamma genes. Analysis of genomic DNA on pulsed field gels using probes isolated from cosmid clones of these genes defined a physical map of 750 kb spanning the CD3 cluster on human chromosome 11q23. The arrangement of these genes suggests that they may share common regulatory elements for the control of gene expression during T-cell ontogeny.
Yunis et al. (1989) identified a breakpoint at 11q23.3 that separated CD3G from ETS1 (164720). This may be the position of the heritable fragile site 11q23.3. They studied a patient with a constitutional deletion (11)(q23.3qter) whose mother and brother had a heritable fragile site 11q23.3. Furthermore, the breakpoint in band 11q23.3 is often found in genomic rearrangements in acute myelogenous leukemia, acute lymphocytic leukemia, and B-cell diffuse lymphoma. Das et al. (1991) demonstrated that CD3G is within 200 kb of the 11q23 breakpoint in translocation t(4;11)(q21;q23) which is associated with acute lymphocytic leukemia, especially in infants. The breakpoint on chromosome 11 is cytogenetically indistinguishable from breakpoints for other leukemia-associated translocations affecting 11q23.
Tunnacliffe and McGuire (1990) found by pulsed field gel electrophoresis that CD3G is separated from the gene for porphobilinogen deaminase (PBGD; 609806) by 750 kb. Several nonrandom translocation chromosomes associated with leukocyte malignancy have breakpoints in this interval.
In 2 Spanish brothers with primary immunodeficiency-17 (IMD17; 615607) with marked differences in severity and outcome (Regueiro et al., 1986), Arnaiz-Villena et al. (1992) identified compound heterozygous truncating mutations in the CD3G gene (186740.0001 and 186740.0002). The younger sib had failure to thrive beginning at age 11 months, recurrent gastrointestinal and respiratory bacterial and viral infections, and bronchiolitis obliterans. He also had an intestinal malabsorption syndrome associated with lack of gut villi and serum gut epithelial cell autoantibodies. The older sib was healthy at age 4 years. Both patients had absent or very low expression of the TCR-CD3 complex on T cells and impaired responses to allogeneic lymphocytes and tetanus toxoid. Lymphocyte numbers were in the normal range. Arnaiz-Villena et al. (1991, 1992) also studied the brothers reported by Regueiro et al. (1986). The younger brother developed autoimmune hemolytic anemia and died at age 31 months after a viral infection. The other brother was healthy at age 10 years.
In 2 Turkish brothers and an unrelated Turkish individual with IMD17, Recio et al. (2007) identified a homozygous truncating mutation in the CD3G gene (K69X; 186740.0003). Haplotype analysis indicated a founder effect. Recio et al. (2007) emphasized the clinical variability of these patients despite similar immunologic findings and noted that lack of the CD3G subunit may be less severe than lack of the CD3E subunit.
In 2 Spanish brothers with immunodeficiency-17 (IMD17; 615607), Arnaiz-Villena et al. (1992) identified 2 independent point mutations in the gene coding for the CD3-gamma protein subunit of the T-cell receptor CD3 complex. The CD3G mRNA shown to be of paternal origin was normal except for a single point mutation, A to G, which changed the methionine initiator codon (ATG) to a valine codon (GTG). The other allele, shown to be of maternal origin, was normal except for the lack of a segment of 17 bp corresponding to the 5-prime end of the third exon of the CD3G gene (186740.0002). The deletion would be expected to shift the reading frame and thus truncate protein translation immediately as a result of the creation of the stop codon. One of the immunodeficient brothers, who was a genetic compound for CD3G mutations and had a severe defect in the expression of the T-cell receptor-CD3 complex, was nonetheless healthy at the age of 10 years, suggesting a redundancy of the immune system and the possibility that fewer receptors may be used by T cells in vivo than expected. However, CD3-gamma may be critical when a series of environmental insults occurs, as suggested by the death of the other brother, who had a severe autoimmune disorder at 31 months of age after a viral infection (Arnaiz-Villena et al., 1991).
For discussion of the 17-bp deletion in the CD3G gene that was found in compound heterozygous state in patients with IMD17 (615607) by Arnaiz-Villena et al. (1992), see 186740.0001.
In 2 Turkish brothers, born of distantly related parents, with severe immunodeficiency-17 (IMD17; 615607), Recio et al. (2007) identified a homozygous c.205A-T transversion in exon 3 of the CD3G gene, resulting in a lys69-to-ter (K69X) substitution. The mutation segregated with the disorder in the family. The patients had recurrent severe infections and inflammatory bowel disease, resulting in death in infancy. An unrelated Turkish boy with a much milder phenotype was also homozygous for the K69X mutation, and haplotype analysis indicated a founder effect. Despite the difference in clinical outcomes, all 3 patients had a similar immunologic profile, with partial T lymphocytopenia and low CD3, but normal B cells, NK cells, and immunoglobulins. Proliferative responses were low compared with controls. All tested patients had very few peripheral blood thymus emigrant cells and decreased TCR rearrangement excision circles (TRECs), whereas the mature memory T-cell pool was essentially normal. These findings suggested that the lack of CD3G impairs thymus production, but not peripheral expansion or accumulation of mature polyclonal T cells.
Arnaiz-Villena, A., Perez-Aciego, P., Ballestin, C., Sotelo, T., Perez-Seoane, C., Martin-Villa, J. M., Regueiro, J. R. Biochemical basis of a novel T lymphocyte receptor immunodeficiency by immunohistochemistry: a possible CD3-gamma abnormality. Lab. Invest. 64: 675-681, 1991. [PubMed: 1709425]
Arnaiz-Villena, A., Timon, M., Corell, A., Perez-Aciego, P., Martin-Villa, J. M., Regueiro, J. R. Primary immunodeficiency caused by mutations in the gene encoding the CD3-gamma subunit of the T-lymphocyte receptor. New Eng. J. Med. 327: 529-533, 1992. [PubMed: 1635567] [Full Text: https://doi.org/10.1056/NEJM199208203270805]
Das, S., Cotter, F. E., Gibbons, B., Dhut, S., Young, B. D. CD3G is within 200 kb of the leukemic t(4;11) translocation breakpoint. Genes Chromosomes Cancer 3: 44-47, 1991. [PubMed: 1829960] [Full Text: https://doi.org/10.1002/gcc.2870030108]
Evans, G. A., Lewis, K. A., Lawless, G. M. Molecular organization of the human CD3 gene family on chromosome 11q23. Immunogenetics 28: 365-373, 1988. [PubMed: 2971614] [Full Text: https://doi.org/10.1007/BF00364236]
Krissansen, G. W., Gorman, P. A., Kozak, C. A., Spurr, N. K., Sheer, D., Goodfellow, P. N., Crumpton, M. J. Chromosomal locations of the gene coding for the CD3 (T3) gamma-subunit of the human and mouse CD3/T-cell antigen receptor complexes. Immunogenetics 26: 258-266, 1987. [PubMed: 2820874] [Full Text: https://doi.org/10.1007/BF00346520]
Krissansen, G. W., Owen, M. J., Verbi, W., Crumpton, M. J. Primary structure of the T3 gamma subunit of the T3/T cell antigen receptor complex deduced from cDNA sequences: evolution of the T3 gamma and delta subunits. EMBO J. 5: 1799-1808, 1986. [PubMed: 2944745] [Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04429.x]
Recio, M. J., Moreno-Pelayo, M. A., Kilic, S. S., Guardo, A. C., Sanal, O., Allende, L. M., Perez-Flores, V., Mencia, A., Modamio-Hoybjor, S., Seoane, E., Regueiro, J. R. Differential biological role of CD3 chains revealed by human immunodeficiencies. J. Immun. 178: 2556-2564, 2007. [PubMed: 17277165] [Full Text: https://doi.org/10.4049/jimmunol.178.4.2556]
Regueiro, J. R., Arnaiz-Villena, A., Ortiz de Landazuri, M., Martin Villa, J. M., Vicario, J. L., Pascual-Ruiz, V., Guerra-Garcia, F., Alcami, J., Lopez-Botet, M., Manzanares, J. Familial defect of CD3 (T3) expression by T cells associated with rare gut epithelial cell autoantibodies. (Letter) Lancet 327: 1274-1275, 1986. Note: Originally Volume I. [PubMed: 2872416] [Full Text: https://doi.org/10.1016/s0140-6736(86)91413-3]
Saito, H., Koyama, T., Georgopoulos, K., Clevers, H., Haser, W. G., LeBien, T., Tonegawa, S., Terhorst, C. Close linkage of the mouse and human CD3 gamma- and delta-chain genes suggests that their transcription is controlled by common regulatory elements. Proc. Nat. Acad. Sci. 84: 9131-9134, 1987. [PubMed: 2827170] [Full Text: https://doi.org/10.1073/pnas.84.24.9131]
Tunnacliffe, A., Buluwela, L., Rabbitts, T. H. Physical linkage of three CD3 genes on human chromosome 11. EMBO J. 6: 2953-2957, 1987. [PubMed: 2826124] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb02600.x]
Tunnacliffe, A., McGuire, R. S. A physical linkage group in human chromosome band 11q23 covering a region implicated in leukocyte neoplasia. Genomics 8: 447-453, 1990. [PubMed: 1981047] [Full Text: https://doi.org/10.1016/0888-7543(90)90030-x]
Tunnacliffe, A., Olsson, C., Buluwela, L., Rabbitts, T. H. Organization of the human CD3 locus on chromosome 11. Europ. J. Immun. 18: 1639-1642, 1988. [PubMed: 2973415] [Full Text: https://doi.org/10.1002/eji.1830181027]
Yunis, J. J., Jones, C., Madden, M. T., Lu, D., Mayer, M. G. Gene order, amplification, and rearrangement of chromosome band 11q23 in hematologic malignancies. Genomics 5: 84-90, 1989. [PubMed: 2527802] [Full Text: https://doi.org/10.1016/0888-7543(89)90090-6]