Entry - *186880 - T-CELL RECEPTOR ALPHA CHAIN CONSTANT REGION; TRAC - OMIM

 
 
* 186880

T-CELL RECEPTOR ALPHA CHAIN CONSTANT REGION; TRAC


HGNC Approved Gene Symbol: TRAC

Cytogenetic location: 14q11.2     Genomic coordinates (GRCh38): 14:22,547,506-22,552,132 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
14q11.2 Immunodeficiency 7, TCR-alpha/beta deficient 615387 AR 3

TEXT

▼ Description

T-lymphocytes recognize antigens via a mechanism that resembles that used by immunoglobulins (Igs; see 147200) produced by B cells. There are 2 main mature T-cell subtypes, those expressing alpha and beta (see TRBC1, 186930) chains, and those expressing gamma (see TRGC1, 186970) and delta (see TRDC, 186810) chains. Unlike secreted Ig molecules, T-cell receptor chains are membrane bound and act through cell-cell contact. The genes encoding the T-cell receptor alpha chain are clustered on chromosome 14. The T-cell receptor alpha chain is formed when 1 of at least 70 variable (V) genes, which encode the N-terminal antigen recognition domain, rearranges to 1 of 61 joining (J) gene segments to create a functional V region exon that is transcribed and spliced to a constant region gene (TRAC) segment encoding the C-terminal portion of the molecule. The lymphoid-specific proteins RAG1 (179615) and RAG2 (179616) direct the V(D)J recombination process in both T and B cells. Following similar synthesis of the beta chain, the alpha and beta chains pair to yield the alpha-beta T-cell receptor heterodimer (Janeway et al., 2005).

▼ Cloning and Expression

T lymphocytes, like B lymphocytes, can recognize a wide range of different antigens. As with B cells, the capability to recognize a given antigen is fixed in any particular clonal line of T cells. However, unlike B cells, T cells recognize antigen in combination with self major histocompatibility complex (MHC) determinants, i.e., the function is 'MHC restricted.' Many authors commented that 'the chemical nature of the T-cell receptors has been elusive' (e.g., Saito et al., 1984). The development of monoclonal antibodies that recognize and precipitate clone-specific proteins on the surface of T cells has provided information on these receptor molecules. Hedrick et al. (1984) approached the molecular genetic study of the previously elusive T-cell antigen receptor with 4 assumptions: that they are expressed in T cells but not in B cells; that the mRNAs for the T-cell receptor proteins should be found on membrane-bound polysomes, the nascent receptor polypeptides being attached to the endoplasmic reticulum by a leader peptide (signal sequence); that like immunoglobulin genes, those that encode the T-cell receptor proteins are rearranged in T cells as a mechanism of generating diversity; and that like immunoglobulin genes, they have constant regions that share some functions and variable regions that confer antigen-binding specificity. They found that a cloned T-cell-specific cDNA showed V, C, and joining J regions remarkably similar in size and sequence to those encoding immunoglobulin proteins.

Hannum et al. (1984) presented the sequence of an alpha chain and pointed to its homology to the immunoglobulin polypeptide chains. The antigen-specific receptors of B lymphocytes and T lymphocytes share many similarities. The receptors of the B cells have long been known to be the Igs. The receptors on T cells consist of immunoglobulin-like integral membrane glycoproteins containing 2 polypeptide subunits, alpha and beta, of similar molecular weight, 40 to 55 kD in the human. Like the Igs of the B cells, each T-cell receptor subunit has, external to the cell membrane, an N-terminal V domain and a C-terminal C domain. Like the Ig genes, the genes for the T-cell receptor subunits are assembled from gene segments which are of at least 3 types for alpha, V, J, and C, and at least 4 for beta, V, diversity (D), J, and C.


▼ Gene Function

See review of the TCR genes by Toyonaga and Mak (1987).

Marrack and Kappler (1987) reviewed the T-cell receptor from the point of view of structure and particularly of function.

Weiss (1990) reviewed the structure and function of the 6-part T-cell antigen receptor complex.

Pestano et al. (1999) identified a differentiative pathway taken by CD8 cells bearing receptors that cannot engage class I MHC (see 142800) self-peptide molecules because of incorrect thymic selection, defects in peripheral MHC class I expression, or antigen presentation. In any of these cases, failed CD8 T-cell receptor coengagement results in downregulation of genes that account for specialized cytolytic T-lymphocyte function and resistance to cell death (CD8-alpha/beta, see 186730; granzyme B, 123910; and LKLF, 602016), and upregulation of Fas (134637) and FasL (134638) death genes. Thus, MHC engagement is required to inhibit expression and delivery of a death program rather than to supply a putative trophic factor for T cell survival. Pestano et al. (1999) hypothesized that defects in delivery of the death signal to these cells underlie the explosive growth and accumulation of double-negative T cells in animals bearing Fas and FasL mutations, in patients that carry inherited mutations of these genes, and in about 25% of systemic lupus erythematosus patients that display the cellular signature of defects in this mechanism of quality control of CD8 cells.

In the thymus, immature thymocytes recognizing self MHC are selected to survive and differentiate through positive selection. Conversely, overtly self-reactive thymocytes are removed through negative selection. Positive selection is mediated in part by the connecting peptide domain (CPM) of TCRA. Backstrom et al. (1998) showed that thymocytes from mice with mutant CPMs were unable to immunoprecipitate CD3D (186790). Werlen et al. (2000) showed that thymocytes from mice with mutant CPMs were unable to activate ERK (MAPK3; 601795) after stimulation with a positively selecting peptide, although other MAPKs that regulate negative selection (e.g., p38, or MAPK14; 600289) and JNK1 (MAPK8; 601158) cascades remained intact. The defect in ERK activation was associated with impaired recruitment of the activated tyrosine kinases LCK (153390) and ZAP70 (176947) and the phosphorylated forms of CD3Z (186780) and the adaptor protein LAT (602354) into detergent-insoluble glycolipid-enriched microdomains (DIGs).

Wu et al. (2002) showed that the TCR interaction with peptide-MHC is initially with the MHC portion, but that subsequently the peptide contacts dominate stabilization, imparting specificity and influencing T cell activation by modulating the duration of TCR binding to peptide-MHC. Wu et al. (2002) concluded that the interaction is functionally subdivided into a 2-step process, such that TCRs efficiently scan diverse peptide-MHC complexes on cell surfaces and that the TCRs are inherently cross-reactive toward different peptides bound by the same MHC.

Seitan et al. (2011) deleted the cohesin locus Rad21 (606462) in mouse thymocytes at a time in development when these cells stop cycling and rearrange their Tcra locus. Rad21-deficient thymocytes had a normal life span and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesin-binding sites flank the TEA promoter and the E-alpha enhancer, and demarcate Tcra from interspersed Tcrd (186810) elements and neighboring housekeeping genes. Cohesin was required for long-range promoter-enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery, and Tcra rearrangement. Provision of prearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. Seitan et al. (2011) concluded that their findings firmly established a cell division-independent role for cohesin in Tcra locus rearrangement and provided a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system.

Using chromosome conformation capture, Shih et al. (2012) demonstrated that the Tcra enhancer (E-alpha) region interacted directly with Trav and Traj gene segments in Cd4 (186940)-positive/Cd8 (see 186910)-positive double-positive (DP) mouse thymocytes. E-alpha promoted interactions between Trav and Traj segments, facilitating their synapsis. Ctcf (604167) bound to E-alpha and to many Tcra/Tcrd locus promoters, biased E-alpha to interact with these promoter elements, and was required for efficient Trav-Traj recombination. Loss of Ctcf in DP thymocytes dysregulated long-distance interactions among these elements, suppressed chromatin hub formation, and impaired initial Trav-Traj rearrangement. Shih et al. (2012) concluded that E-alpha and CTCF cooperate to create a developmentally regulated chromatin hub that supports TRAV-TRAJ synapsis and recombination.

Choudhuri et al. (2014) showed that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunologic synapse center. Tumor susceptibility gene-101 (TSG101; 601387) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting-4 (VPS4; 609982) mediates scission of microvesicles from the T-cell plasma membrane. The HIV polyprotein Gag coopts this process for budding of virus-like particles. B cells bearing cognate pathogens bound to major histocompatibility complex molecules (pMHC) receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. Choudhuri et al. (2014) concluded that the immunologic synapse orchestrates TCR sorting and release in extracellular microvesicles and that these microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on antigen-presenting cells.


▼ Gene Structure

Saito et al. (1984) presented the complete deduced primary structure of the T-cell receptor.

Siu et al. (1984) stated that the 'T-cell antigen receptor appears to be assembled from 3 gene segments, V, D, and J, and accordingly most closely resembles immunoglobulin heavy chain V genes.'

Studies in both mouse and man show that the TCR-delta gene (TCRD; 186810) lies within the TCRA locus, upstream from the estimated 50 to 100 J(alpha) segments and between V(alpha) and J(alpha). Whereas TCRD genes rearrange early in thymic ontogeny, TCRA genes rearrange much later. Further, the utilization of V segments appears to be selective. Satyanarayana et al. (1988) analyzed the germline organization of the TCR-alpha/delta locus. Koop et al. (1994) sequenced and analyzed 97.6 kb of DNA containing the TCRA constant gene and the TCRD constant gene as well as the TCRDV3 and 61 different TCRAJ gene segments and compared the organization and structure to the same, previously described region in the mouse. They concluded that this region of the human and mouse genomes is remarkably conserved.

Weiss (1990) presented useful diagrams of the structural domains of the receptor proteins (his Figure 1) and of the organization and rearrangement of the T-cell receptor genes (his Figure 2).

Harvey and Showe (1993) pointed out that nearly 60 unique J regions had been identified in TCR-alpha chains, yet fewer than one-third of these had been localized within the TCRA gene. They reported a rapid method for mapping productively rearranged J-alpha regions.

Janeway et al. (2005) summarized the germline organization of the human TCR-alpha locus. The TCR-alpha locus contains 70 to 80 V gene segments, each preceded by an exon encoding the leader sequence. The V gene cluster is followed, at a considerable distance, by a cluster of 61 J gene segments, and then by a single constant region gene, TRAC. The TRAC gene contains separate exons encoding the constant and hinge domains and a single exon encoding the transmembrane and cytoplasmic region. The TCR-delta locus is located entirely within the TCR-alpha locus, primarily between the V and J gene clusters.

▼ Mapping

In the rat, Binz et al. (1976) showed linkage between heavy chain immunoglobulin genes and idiotypic T-cell receptors with specificity for MHC antigens but lack of linkage with MHC genes and with kappa light chain genes. If homology exists in man, a likely situation, then a T-cell receptor locus is linked to the Gm loci (147100-147130), which have been mapped to 14q34.

In the mouse the alpha subunit is coded by chromosome 14 (Kranz et al., 1985).

Barker et al. (1985) assigned the TCRA locus to human chromosome 14, proximal to 14q21. Human chromosome 14 appears to contain 2 regions of syntenic homology to mouse chromosomes: a proximal segment with TCRA and PNP (164050) which are on mouse 14 and a distal segment with oncogene FOS (164810) and IGH (147100) which are on mouse 12.

By somatic cell hybridization, Croce et al. (1985) assigned the TCRA gene to chromosome 14 and by in situ hybridization further narrowed the assignment to 14q11-14q12. This site is consistently involved in translocations and inversions detectable in human T-cell leukemias and lymphomas. Specifically, an inversion of the segment 14q11.2-q32.2 occurs in T-cell chronic lymphatic leukemia and a t(14;14)(q11;q32) translocation occurs in T-cell malignancies of patients with ataxia-telangiectasia (208900) (McCaw et al., 1975). These observations led Croce et al. (1985) to suggest that the oncogene for which they proposed the designation tcl-1 (186960) is located on band 14q32.3 and becomes activated when it is in proximity to the TCRA gene.

Like the beta chain (186930) of the T-cell antigen receptor, the alpha chain is encoded in separate noncontiguous gene segments, V, J, and C. Using an alpha chain cDNA probe of DNA from somatic cell hybrids, Jones et al. (1985) assigned the gene to chromosome 14. From study of a deletion segregant containing only the distal half of chromosome 14 (14q22-qter), they concluded that the alpha locus is situated proximal to 14q22. They pointed out the high frequency of breaks in the 14q11-q13 segment, possibly involving the alpha locus in T-cell malignancies, and leading Hecht et al. (1984) to suggest the existence of genes relating to T-cell function in this region.

By analysis of a translocation t(11;14)(p13;q11) in 2 cases of T-cell leukemia, Erikson et al. (1985) showed that the TCR-alpha locus is on chromosome 14q11.2, with the V segments proximal to the C segment. Lewis et al. (1985) reported identical findings.


▼ Cytogenetics

Erikson et al. (1985) showed that the TCRA gene was split by chromosome translocation t(11;14)(p13;q11) in 2 cases of T-cell leukemia. The constant segment was translocated to chromosome 11 whereas the variable region remained on chromosome 14. Thus, the V segments are proximal to the C segment within band 14q11.2. Lewis et al. (1985) reported identical findings.

In cases of adult T-cell leukemia in Nagasaki Prefecture of Japan, an area of high frequency, Sadamori et al. (1985) found abnormalities at band 14q11. This form of leukemia is associated with HTLV/ATLV viruses. Thus, 14q32 is associated with B-cell lymphoma/leukemia and 14q11 with T-cell lymphoma/leukemia including Sezary syndrome and mycosis fungoides.

In an inversion of chromosome 14, inv(14)(q11;q32), in a T cell lymphoma, Baer et al. (1985) showed that on the normal chromosome 14, a V(alpha) segment had rearranged with a J(alpha) segment. In contrast, the inverted chromosome featured an unprecedented rearrangement in which a V-heavy chain segment from 14q32 (147070) had joined with a J(alpha) segment from 14q11. The V(H)-J(alpha)C(alpha) rearrangement was productive at the genomic level and presumably encodes a hybrid immunoglobulin/T cell receptor polypeptide.

The MOLT-16 cell line, which was established from the malignant cells of a patient with T-cell acute lymphoblastic leukemia, carries a translocation t(8;14)(q24;q11). By molecular approaches using the MOLT-16 cell line, McKeithan et al. (1986) showed that the breakpoint on 14 occurred close to a joining sequence (J) of the TCRA gene and that the constant region and part of the J region of TCRA are translocated to the 3-prime side of the MYC gene.

Le Beau et al. (1986) demonstrated that the TCRA gene was split in a cell line from a child with T-cell acute lymphoblastic leukemia and a t(11;14)(p15;q11). With in situ chromosomal hybridization and with Southern blot analysis, they showed that the break at 14q11 occurred within the variable region of TCRA; the break at 11p15 occurred between the HRAS1 gene (190020) and the genes for insulin and IGF2.

By studies of cells from a person with T-cell acute lymphocytic leukemia and a t(10;14) translocation, Kagan et al. (1987) demonstrated that the break in chromosome 14 had occurred in the TCRA locus in a region between the variable and constant genes. The break in chromosome 10 was at 10q24. The derivative 10q+ chromosome retained the human gene for terminal deoxynucleotidyltransferase (TDT; 187410), which has been mapped to 10q23-q25. These results suggested to Kagan et al. (1987) that the translocation of the TCRA constant locus to a putative cellular protooncogene located proximal to the breakpoint at 10q24, for which they proposed the name TCL3 (186770), had resulted in deregulation of said oncogene, leading to T-cell leukemia. Evidence suggested also that the TDT gene is located proximal to TCL3 at band 10q23-q24.


▼ Molecular Genetics

T-Cell Receptor Alpha Chain Polymorphisms

Klein et al. (1987) found considerable variability in the V region and J sequences of the TCRA gene.

Posnett et al. (1986) used 3 different murine monoclonal antibodies to human clonotypic T-cell antigen receptor to demonstrate inherited polymorphism comparable to the allotypic polymorphism of immunoglobulins. Restriction fragment length polymorphisms had previously been identified in human alpha and beta chain genes. These RFLPs mapped to introns; obviously, the polymorphism demonstrated with monoclonal antibodies involved exons. The authors suspected that the polymorphism represented an allotypic system of a variable or joining region. Their results indicated that allelic exclusion governs the expression of the clonotypic receptor by human T-cells and thus is a phenomenon not limited to immunoglobulin-producing cells. Robinson and Kindt (1987) identified 'hotspots' of recombination in the TCRA complex by studying the segregation of 3 RFLPs associated with the C region and 3 RFLPs associated with the V region in 8 families. Oksenberg et al. (1989) found an association between polymorphic markers in the variable and constant regions of the TCR-alpha gene and both multiple sclerosis (126200) and myasthenia gravis (254200).

Moffatt et al. (2000) examined linkage disequilibrium (LD) within an 850-kb section of the TCR-alpha/delta locus by genotyping 159 families at 24 V-gene segment single-nucleotide polymorphisms (SNPs) and 2 microsatellites. Significant LD was relatively common at 250 kb and was detectable beyond 500 kb, a much greater distance than suggested by simulations. The mean extent of LD was twice as far between alleles of low frequency than between common alleles, and distribution was highly irregular and concentrated in 3 distinct islands. The authors suggested that, if these data are typical of other genomic regions, the minimum number of markers necessary for comprehensive LD mapping of the genome may be reduced by at least an order of magnitude.

Immunodeficiency 7

In 2 unrelated Pakistani patients with immunodeficiency-7 (IMD7; 615387), Morgan et al. (2011) identified a homozygous G-to-A transition at the first nucleotide immediately following the termination codon in exon 3 of the TRAC gene (c.Ter1G-A; 186880.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the families and was not found in 384 control chromosomes. The mutation caused aberrant splicing and an elongated translation product (Thr107LeufsTer56), resulting in loss of significant transmembrane and cytoplasmic domains of the TCR-alpha chain. Whereas control cells showed colocalization of alpha- and beta-TCR chains, patient cells showed reduced levels of expression and no evidence of colocalization, suggesting that the mutant alpha chain fails to complex normally with the TCR-beta chain.

In 3 sibs, born of unrelated Indian parents, with IMD7, Rawat et al. (2021) identified the same homozygous G-to-A transition in the last nucleotide of exon 3 of the TRAC gene as that identified by Morgan et al. (2011). The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of DNA rearrangements at the TCR-alpha (TRA) locus showed an unusual pattern, with preferential usage of distal TRAV and TRAJ segments. The TCR-beta (TRB) locus did not show abnormal gene rearrangement patterns. Rawat et al. (2021) postulated that the inability of patients with mutant TRAC to express a functional TCR-alpha/beta receptor may induce developing thymocytes to continually rearrange the TRA locus, even though no functional TCR-alpha protein is expressed on the cell membrane.

Associations Pending Confirmation

For discussion of a possible association between variation in the TCRA gene and narcolepsy, see NRCLP5 (612851).

▼ History

The TCR-alpha and TCR-gamma (TCRG; 186970) glycoprotein chains are encoded by discrete variable (V), junctional (J), and constant (C) genes. (The TCR-beta and TCR-delta chains have additional diversity (D) segments.) The precise number of V-alpha segments in the germline is unknown, but sequence analyses of cDNA clones from a number of individuals have identified 100 different sequences, which can be grouped into 32 subgroups containing sequences sharing greater than, or equal to, 75% homology. During T-cell development the TCR genes rearrange to produce a contiguous V--(D)--J exon. Subsequent splicing of the transcript joins the J and C genes, and the mature mRNA is translated into a complete polypeptide chain. The multiplicity of V, (D), and J segments and the random nature of the V--(D)--J recombination, in addition to junctional variation produced by the enzyme terminal transferase (187410) (termed N region diversity), enable the germline repertoire to generate an estimated 10(15) different alpha/beta TCRs (summary by Davis and Bjorkman, 1988).


▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001 IMMUNODEFICIENCY 7

TRAC, TER1G-A
  
RCV000054556

In 2 unrelated Pakistani patients with immunodeficiency-7 (IMD7; 615387), Morgan et al. (2011) identified a homozygous G-to-A transition at the first nucleotide immediately following the termination codon in exon 3 of the TRAC gene (c.Ter1G-A). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder and was not found in 384 control chromosomes. The mutation was located in the consensus 5-prime splice site, and RT-PCR analysis of affected individuals showed that the mutation caused the skipping of exon 3, resulting in an aberrant transcript joining exon 2 to the normally untranslated exon 4. The predicted translation product would have the 35 C-terminal amino acids replaced by 56 amino acids encoded by exon 4 (Thr107LeufsTer56), resulting in loss of significant transmembrane and cytoplasmic domains of the TCR-alpha chain. The patients presented in the first years of life with recurrent infections, lymphadenopathy, and failure to thrive associated with T-cell dysfunction and normal humoral immunity. One child had severe herpes and EBV infections. Both children had evidence of immune dysregulation, including autoantibodies and hypereosinophilia. Both underwent bone marrow transplantation. Flow cytometric analysis showed presence of CD3+ T cells, but these cells uniformly expressed TCR-gamma/delta, with little or no TCR-alpha/beta expression.

In 3 sibs, born of unrelated Indian parents, with IMD7, Rawat et al. (2021) identified the same homozygous G-to-A transition in the last nucleotide of exon 3 of the TRAC gene as that identified by Morgan et al. (2011). The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of DNA rearrangements at the TCR-alpha (TRA) locus showed an unusual pattern, with preferential usage of distal TRAV and TRAJ segments. The TCR-beta (TRB) locus did not show abnormal gene rearrangement patterns. The findings suggested a founder effect for this geographical region.


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  46. Shih, H.-Y., Verma-Gaur, J., Torkamani, A., Feeney, A. J., Galjart, N., Krangel, M. S. Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub. Proc. Nat. Acad. Sci. 109: E3493-E3502, 2012. Note: Electronic Article. [PubMed: 23169622, images, related citations] [Full Text]

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Contributors:
Cassandra L. Kniffin - updated : 11/17/2021
Ada Hamosh - updated : 3/28/2014
Paul J. Converse - updated : 11/6/2013
Matthew B. Gross - updated : 9/30/2013
Paul J. Converse - updated : 9/30/2013
Cassandra L. Kniffin - updated : 8/29/2013
Ada Hamosh - updated : 9/21/2011
Paul J. Converse - updated : 7/31/2002
Paul J. Converse - updated : 8/18/2000
George E. Tiller - updated : 5/2/2000
Ada Hamosh - updated : 5/13/1999
Creation Date:
Victor A. McKusick : 6/2/1986
Edit History:
carol : 11/22/2021
alopez : 11/19/2021
ckniffin : 11/17/2021
carol : 08/14/2020
carol : 07/09/2016
carol : 12/30/2015
alopez : 3/28/2014
mgross : 11/12/2013
mcolton : 11/6/2013
mgross : 10/4/2013
mgross : 10/3/2013
mgross : 9/30/2013
mgross : 9/30/2013
mgross : 9/30/2013
mgross : 9/30/2013
mgross : 9/30/2013
mgross : 9/30/2013
mgross : 9/30/2013
carol : 8/30/2013
carol : 8/30/2013
carol : 8/30/2013
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terry : 8/8/2012
alopez : 3/7/2012
carol : 11/22/2011
alopez : 9/23/2011
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carol : 12/17/2009
alopez : 12/16/2009
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ckniffin : 6/12/2009
alopez : 5/13/2009
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alopez : 11/14/2003
alopez : 7/31/2002
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mgross : 8/21/2000
mgross : 8/18/2000
alopez : 5/2/2000
alopez : 5/13/1999
terry : 5/13/1999
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alopez : 5/15/1998
mark : 8/15/1997
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carol : 3/14/1994
carol : 12/23/1993
carol : 11/17/1993

* 186880

T-CELL RECEPTOR ALPHA CHAIN CONSTANT REGION; TRAC


HGNC Approved Gene Symbol: TRAC

Cytogenetic location: 14q11.2     Genomic coordinates (GRCh38): 14:22,547,506-22,552,132 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
14q11.2 Immunodeficiency 7, TCR-alpha/beta deficient 615387 Autosomal recessive 3

TEXT

Description

T-lymphocytes recognize antigens via a mechanism that resembles that used by immunoglobulins (Igs; see 147200) produced by B cells. There are 2 main mature T-cell subtypes, those expressing alpha and beta (see TRBC1, 186930) chains, and those expressing gamma (see TRGC1, 186970) and delta (see TRDC, 186810) chains. Unlike secreted Ig molecules, T-cell receptor chains are membrane bound and act through cell-cell contact. The genes encoding the T-cell receptor alpha chain are clustered on chromosome 14. The T-cell receptor alpha chain is formed when 1 of at least 70 variable (V) genes, which encode the N-terminal antigen recognition domain, rearranges to 1 of 61 joining (J) gene segments to create a functional V region exon that is transcribed and spliced to a constant region gene (TRAC) segment encoding the C-terminal portion of the molecule. The lymphoid-specific proteins RAG1 (179615) and RAG2 (179616) direct the V(D)J recombination process in both T and B cells. Following similar synthesis of the beta chain, the alpha and beta chains pair to yield the alpha-beta T-cell receptor heterodimer (Janeway et al., 2005).

Cloning and Expression

T lymphocytes, like B lymphocytes, can recognize a wide range of different antigens. As with B cells, the capability to recognize a given antigen is fixed in any particular clonal line of T cells. However, unlike B cells, T cells recognize antigen in combination with self major histocompatibility complex (MHC) determinants, i.e., the function is 'MHC restricted.' Many authors commented that 'the chemical nature of the T-cell receptors has been elusive' (e.g., Saito et al., 1984). The development of monoclonal antibodies that recognize and precipitate clone-specific proteins on the surface of T cells has provided information on these receptor molecules. Hedrick et al. (1984) approached the molecular genetic study of the previously elusive T-cell antigen receptor with 4 assumptions: that they are expressed in T cells but not in B cells; that the mRNAs for the T-cell receptor proteins should be found on membrane-bound polysomes, the nascent receptor polypeptides being attached to the endoplasmic reticulum by a leader peptide (signal sequence); that like immunoglobulin genes, those that encode the T-cell receptor proteins are rearranged in T cells as a mechanism of generating diversity; and that like immunoglobulin genes, they have constant regions that share some functions and variable regions that confer antigen-binding specificity. They found that a cloned T-cell-specific cDNA showed V, C, and joining J regions remarkably similar in size and sequence to those encoding immunoglobulin proteins.

Hannum et al. (1984) presented the sequence of an alpha chain and pointed to its homology to the immunoglobulin polypeptide chains. The antigen-specific receptors of B lymphocytes and T lymphocytes share many similarities. The receptors of the B cells have long been known to be the Igs. The receptors on T cells consist of immunoglobulin-like integral membrane glycoproteins containing 2 polypeptide subunits, alpha and beta, of similar molecular weight, 40 to 55 kD in the human. Like the Igs of the B cells, each T-cell receptor subunit has, external to the cell membrane, an N-terminal V domain and a C-terminal C domain. Like the Ig genes, the genes for the T-cell receptor subunits are assembled from gene segments which are of at least 3 types for alpha, V, J, and C, and at least 4 for beta, V, diversity (D), J, and C.


Gene Function

See review of the TCR genes by Toyonaga and Mak (1987).

Marrack and Kappler (1987) reviewed the T-cell receptor from the point of view of structure and particularly of function.

Weiss (1990) reviewed the structure and function of the 6-part T-cell antigen receptor complex.

Pestano et al. (1999) identified a differentiative pathway taken by CD8 cells bearing receptors that cannot engage class I MHC (see 142800) self-peptide molecules because of incorrect thymic selection, defects in peripheral MHC class I expression, or antigen presentation. In any of these cases, failed CD8 T-cell receptor coengagement results in downregulation of genes that account for specialized cytolytic T-lymphocyte function and resistance to cell death (CD8-alpha/beta, see 186730; granzyme B, 123910; and LKLF, 602016), and upregulation of Fas (134637) and FasL (134638) death genes. Thus, MHC engagement is required to inhibit expression and delivery of a death program rather than to supply a putative trophic factor for T cell survival. Pestano et al. (1999) hypothesized that defects in delivery of the death signal to these cells underlie the explosive growth and accumulation of double-negative T cells in animals bearing Fas and FasL mutations, in patients that carry inherited mutations of these genes, and in about 25% of systemic lupus erythematosus patients that display the cellular signature of defects in this mechanism of quality control of CD8 cells.

In the thymus, immature thymocytes recognizing self MHC are selected to survive and differentiate through positive selection. Conversely, overtly self-reactive thymocytes are removed through negative selection. Positive selection is mediated in part by the connecting peptide domain (CPM) of TCRA. Backstrom et al. (1998) showed that thymocytes from mice with mutant CPMs were unable to immunoprecipitate CD3D (186790). Werlen et al. (2000) showed that thymocytes from mice with mutant CPMs were unable to activate ERK (MAPK3; 601795) after stimulation with a positively selecting peptide, although other MAPKs that regulate negative selection (e.g., p38, or MAPK14; 600289) and JNK1 (MAPK8; 601158) cascades remained intact. The defect in ERK activation was associated with impaired recruitment of the activated tyrosine kinases LCK (153390) and ZAP70 (176947) and the phosphorylated forms of CD3Z (186780) and the adaptor protein LAT (602354) into detergent-insoluble glycolipid-enriched microdomains (DIGs).

Wu et al. (2002) showed that the TCR interaction with peptide-MHC is initially with the MHC portion, but that subsequently the peptide contacts dominate stabilization, imparting specificity and influencing T cell activation by modulating the duration of TCR binding to peptide-MHC. Wu et al. (2002) concluded that the interaction is functionally subdivided into a 2-step process, such that TCRs efficiently scan diverse peptide-MHC complexes on cell surfaces and that the TCRs are inherently cross-reactive toward different peptides bound by the same MHC.

Seitan et al. (2011) deleted the cohesin locus Rad21 (606462) in mouse thymocytes at a time in development when these cells stop cycling and rearrange their Tcra locus. Rad21-deficient thymocytes had a normal life span and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesin-binding sites flank the TEA promoter and the E-alpha enhancer, and demarcate Tcra from interspersed Tcrd (186810) elements and neighboring housekeeping genes. Cohesin was required for long-range promoter-enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery, and Tcra rearrangement. Provision of prearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. Seitan et al. (2011) concluded that their findings firmly established a cell division-independent role for cohesin in Tcra locus rearrangement and provided a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system.

Using chromosome conformation capture, Shih et al. (2012) demonstrated that the Tcra enhancer (E-alpha) region interacted directly with Trav and Traj gene segments in Cd4 (186940)-positive/Cd8 (see 186910)-positive double-positive (DP) mouse thymocytes. E-alpha promoted interactions between Trav and Traj segments, facilitating their synapsis. Ctcf (604167) bound to E-alpha and to many Tcra/Tcrd locus promoters, biased E-alpha to interact with these promoter elements, and was required for efficient Trav-Traj recombination. Loss of Ctcf in DP thymocytes dysregulated long-distance interactions among these elements, suppressed chromatin hub formation, and impaired initial Trav-Traj rearrangement. Shih et al. (2012) concluded that E-alpha and CTCF cooperate to create a developmentally regulated chromatin hub that supports TRAV-TRAJ synapsis and recombination.

Choudhuri et al. (2014) showed that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunologic synapse center. Tumor susceptibility gene-101 (TSG101; 601387) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting-4 (VPS4; 609982) mediates scission of microvesicles from the T-cell plasma membrane. The HIV polyprotein Gag coopts this process for budding of virus-like particles. B cells bearing cognate pathogens bound to major histocompatibility complex molecules (pMHC) receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. Choudhuri et al. (2014) concluded that the immunologic synapse orchestrates TCR sorting and release in extracellular microvesicles and that these microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on antigen-presenting cells.


Gene Structure

Saito et al. (1984) presented the complete deduced primary structure of the T-cell receptor.

Siu et al. (1984) stated that the 'T-cell antigen receptor appears to be assembled from 3 gene segments, V, D, and J, and accordingly most closely resembles immunoglobulin heavy chain V genes.'

Studies in both mouse and man show that the TCR-delta gene (TCRD; 186810) lies within the TCRA locus, upstream from the estimated 50 to 100 J(alpha) segments and between V(alpha) and J(alpha). Whereas TCRD genes rearrange early in thymic ontogeny, TCRA genes rearrange much later. Further, the utilization of V segments appears to be selective. Satyanarayana et al. (1988) analyzed the germline organization of the TCR-alpha/delta locus. Koop et al. (1994) sequenced and analyzed 97.6 kb of DNA containing the TCRA constant gene and the TCRD constant gene as well as the TCRDV3 and 61 different TCRAJ gene segments and compared the organization and structure to the same, previously described region in the mouse. They concluded that this region of the human and mouse genomes is remarkably conserved.

Weiss (1990) presented useful diagrams of the structural domains of the receptor proteins (his Figure 1) and of the organization and rearrangement of the T-cell receptor genes (his Figure 2).

Harvey and Showe (1993) pointed out that nearly 60 unique J regions had been identified in TCR-alpha chains, yet fewer than one-third of these had been localized within the TCRA gene. They reported a rapid method for mapping productively rearranged J-alpha regions.

Janeway et al. (2005) summarized the germline organization of the human TCR-alpha locus. The TCR-alpha locus contains 70 to 80 V gene segments, each preceded by an exon encoding the leader sequence. The V gene cluster is followed, at a considerable distance, by a cluster of 61 J gene segments, and then by a single constant region gene, TRAC. The TRAC gene contains separate exons encoding the constant and hinge domains and a single exon encoding the transmembrane and cytoplasmic region. The TCR-delta locus is located entirely within the TCR-alpha locus, primarily between the V and J gene clusters.

Mapping

In the rat, Binz et al. (1976) showed linkage between heavy chain immunoglobulin genes and idiotypic T-cell receptors with specificity for MHC antigens but lack of linkage with MHC genes and with kappa light chain genes. If homology exists in man, a likely situation, then a T-cell receptor locus is linked to the Gm loci (147100-147130), which have been mapped to 14q34.

In the mouse the alpha subunit is coded by chromosome 14 (Kranz et al., 1985).

Barker et al. (1985) assigned the TCRA locus to human chromosome 14, proximal to 14q21. Human chromosome 14 appears to contain 2 regions of syntenic homology to mouse chromosomes: a proximal segment with TCRA and PNP (164050) which are on mouse 14 and a distal segment with oncogene FOS (164810) and IGH (147100) which are on mouse 12.

By somatic cell hybridization, Croce et al. (1985) assigned the TCRA gene to chromosome 14 and by in situ hybridization further narrowed the assignment to 14q11-14q12. This site is consistently involved in translocations and inversions detectable in human T-cell leukemias and lymphomas. Specifically, an inversion of the segment 14q11.2-q32.2 occurs in T-cell chronic lymphatic leukemia and a t(14;14)(q11;q32) translocation occurs in T-cell malignancies of patients with ataxia-telangiectasia (208900) (McCaw et al., 1975). These observations led Croce et al. (1985) to suggest that the oncogene for which they proposed the designation tcl-1 (186960) is located on band 14q32.3 and becomes activated when it is in proximity to the TCRA gene.

Like the beta chain (186930) of the T-cell antigen receptor, the alpha chain is encoded in separate noncontiguous gene segments, V, J, and C. Using an alpha chain cDNA probe of DNA from somatic cell hybrids, Jones et al. (1985) assigned the gene to chromosome 14. From study of a deletion segregant containing only the distal half of chromosome 14 (14q22-qter), they concluded that the alpha locus is situated proximal to 14q22. They pointed out the high frequency of breaks in the 14q11-q13 segment, possibly involving the alpha locus in T-cell malignancies, and leading Hecht et al. (1984) to suggest the existence of genes relating to T-cell function in this region.

By analysis of a translocation t(11;14)(p13;q11) in 2 cases of T-cell leukemia, Erikson et al. (1985) showed that the TCR-alpha locus is on chromosome 14q11.2, with the V segments proximal to the C segment. Lewis et al. (1985) reported identical findings.


Cytogenetics

Erikson et al. (1985) showed that the TCRA gene was split by chromosome translocation t(11;14)(p13;q11) in 2 cases of T-cell leukemia. The constant segment was translocated to chromosome 11 whereas the variable region remained on chromosome 14. Thus, the V segments are proximal to the C segment within band 14q11.2. Lewis et al. (1985) reported identical findings.

In cases of adult T-cell leukemia in Nagasaki Prefecture of Japan, an area of high frequency, Sadamori et al. (1985) found abnormalities at band 14q11. This form of leukemia is associated with HTLV/ATLV viruses. Thus, 14q32 is associated with B-cell lymphoma/leukemia and 14q11 with T-cell lymphoma/leukemia including Sezary syndrome and mycosis fungoides.

In an inversion of chromosome 14, inv(14)(q11;q32), in a T cell lymphoma, Baer et al. (1985) showed that on the normal chromosome 14, a V(alpha) segment had rearranged with a J(alpha) segment. In contrast, the inverted chromosome featured an unprecedented rearrangement in which a V-heavy chain segment from 14q32 (147070) had joined with a J(alpha) segment from 14q11. The V(H)-J(alpha)C(alpha) rearrangement was productive at the genomic level and presumably encodes a hybrid immunoglobulin/T cell receptor polypeptide.

The MOLT-16 cell line, which was established from the malignant cells of a patient with T-cell acute lymphoblastic leukemia, carries a translocation t(8;14)(q24;q11). By molecular approaches using the MOLT-16 cell line, McKeithan et al. (1986) showed that the breakpoint on 14 occurred close to a joining sequence (J) of the TCRA gene and that the constant region and part of the J region of TCRA are translocated to the 3-prime side of the MYC gene.

Le Beau et al. (1986) demonstrated that the TCRA gene was split in a cell line from a child with T-cell acute lymphoblastic leukemia and a t(11;14)(p15;q11). With in situ chromosomal hybridization and with Southern blot analysis, they showed that the break at 14q11 occurred within the variable region of TCRA; the break at 11p15 occurred between the HRAS1 gene (190020) and the genes for insulin and IGF2.

By studies of cells from a person with T-cell acute lymphocytic leukemia and a t(10;14) translocation, Kagan et al. (1987) demonstrated that the break in chromosome 14 had occurred in the TCRA locus in a region between the variable and constant genes. The break in chromosome 10 was at 10q24. The derivative 10q+ chromosome retained the human gene for terminal deoxynucleotidyltransferase (TDT; 187410), which has been mapped to 10q23-q25. These results suggested to Kagan et al. (1987) that the translocation of the TCRA constant locus to a putative cellular protooncogene located proximal to the breakpoint at 10q24, for which they proposed the name TCL3 (186770), had resulted in deregulation of said oncogene, leading to T-cell leukemia. Evidence suggested also that the TDT gene is located proximal to TCL3 at band 10q23-q24.


Molecular Genetics

T-Cell Receptor Alpha Chain Polymorphisms

Klein et al. (1987) found considerable variability in the V region and J sequences of the TCRA gene.

Posnett et al. (1986) used 3 different murine monoclonal antibodies to human clonotypic T-cell antigen receptor to demonstrate inherited polymorphism comparable to the allotypic polymorphism of immunoglobulins. Restriction fragment length polymorphisms had previously been identified in human alpha and beta chain genes. These RFLPs mapped to introns; obviously, the polymorphism demonstrated with monoclonal antibodies involved exons. The authors suspected that the polymorphism represented an allotypic system of a variable or joining region. Their results indicated that allelic exclusion governs the expression of the clonotypic receptor by human T-cells and thus is a phenomenon not limited to immunoglobulin-producing cells. Robinson and Kindt (1987) identified 'hotspots' of recombination in the TCRA complex by studying the segregation of 3 RFLPs associated with the C region and 3 RFLPs associated with the V region in 8 families. Oksenberg et al. (1989) found an association between polymorphic markers in the variable and constant regions of the TCR-alpha gene and both multiple sclerosis (126200) and myasthenia gravis (254200).

Moffatt et al. (2000) examined linkage disequilibrium (LD) within an 850-kb section of the TCR-alpha/delta locus by genotyping 159 families at 24 V-gene segment single-nucleotide polymorphisms (SNPs) and 2 microsatellites. Significant LD was relatively common at 250 kb and was detectable beyond 500 kb, a much greater distance than suggested by simulations. The mean extent of LD was twice as far between alleles of low frequency than between common alleles, and distribution was highly irregular and concentrated in 3 distinct islands. The authors suggested that, if these data are typical of other genomic regions, the minimum number of markers necessary for comprehensive LD mapping of the genome may be reduced by at least an order of magnitude.

Immunodeficiency 7

In 2 unrelated Pakistani patients with immunodeficiency-7 (IMD7; 615387), Morgan et al. (2011) identified a homozygous G-to-A transition at the first nucleotide immediately following the termination codon in exon 3 of the TRAC gene (c.Ter1G-A; 186880.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the families and was not found in 384 control chromosomes. The mutation caused aberrant splicing and an elongated translation product (Thr107LeufsTer56), resulting in loss of significant transmembrane and cytoplasmic domains of the TCR-alpha chain. Whereas control cells showed colocalization of alpha- and beta-TCR chains, patient cells showed reduced levels of expression and no evidence of colocalization, suggesting that the mutant alpha chain fails to complex normally with the TCR-beta chain.

In 3 sibs, born of unrelated Indian parents, with IMD7, Rawat et al. (2021) identified the same homozygous G-to-A transition in the last nucleotide of exon 3 of the TRAC gene as that identified by Morgan et al. (2011). The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of DNA rearrangements at the TCR-alpha (TRA) locus showed an unusual pattern, with preferential usage of distal TRAV and TRAJ segments. The TCR-beta (TRB) locus did not show abnormal gene rearrangement patterns. Rawat et al. (2021) postulated that the inability of patients with mutant TRAC to express a functional TCR-alpha/beta receptor may induce developing thymocytes to continually rearrange the TRA locus, even though no functional TCR-alpha protein is expressed on the cell membrane.

Associations Pending Confirmation

For discussion of a possible association between variation in the TCRA gene and narcolepsy, see NRCLP5 (612851).

History

The TCR-alpha and TCR-gamma (TCRG; 186970) glycoprotein chains are encoded by discrete variable (V), junctional (J), and constant (C) genes. (The TCR-beta and TCR-delta chains have additional diversity (D) segments.) The precise number of V-alpha segments in the germline is unknown, but sequence analyses of cDNA clones from a number of individuals have identified 100 different sequences, which can be grouped into 32 subgroups containing sequences sharing greater than, or equal to, 75% homology. During T-cell development the TCR genes rearrange to produce a contiguous V--(D)--J exon. Subsequent splicing of the transcript joins the J and C genes, and the mature mRNA is translated into a complete polypeptide chain. The multiplicity of V, (D), and J segments and the random nature of the V--(D)--J recombination, in addition to junctional variation produced by the enzyme terminal transferase (187410) (termed N region diversity), enable the germline repertoire to generate an estimated 10(15) different alpha/beta TCRs (summary by Davis and Bjorkman, 1988).


ALLELIC VARIANTS 1 Selected Example):

.0001   IMMUNODEFICIENCY 7

TRAC, TER1G-A
SNP: rs397514259, ClinVar: RCV000054556

In 2 unrelated Pakistani patients with immunodeficiency-7 (IMD7; 615387), Morgan et al. (2011) identified a homozygous G-to-A transition at the first nucleotide immediately following the termination codon in exon 3 of the TRAC gene (c.Ter1G-A). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder and was not found in 384 control chromosomes. The mutation was located in the consensus 5-prime splice site, and RT-PCR analysis of affected individuals showed that the mutation caused the skipping of exon 3, resulting in an aberrant transcript joining exon 2 to the normally untranslated exon 4. The predicted translation product would have the 35 C-terminal amino acids replaced by 56 amino acids encoded by exon 4 (Thr107LeufsTer56), resulting in loss of significant transmembrane and cytoplasmic domains of the TCR-alpha chain. The patients presented in the first years of life with recurrent infections, lymphadenopathy, and failure to thrive associated with T-cell dysfunction and normal humoral immunity. One child had severe herpes and EBV infections. Both children had evidence of immune dysregulation, including autoantibodies and hypereosinophilia. Both underwent bone marrow transplantation. Flow cytometric analysis showed presence of CD3+ T cells, but these cells uniformly expressed TCR-gamma/delta, with little or no TCR-alpha/beta expression.

In 3 sibs, born of unrelated Indian parents, with IMD7, Rawat et al. (2021) identified the same homozygous G-to-A transition in the last nucleotide of exon 3 of the TRAC gene as that identified by Morgan et al. (2011). The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of DNA rearrangements at the TCR-alpha (TRA) locus showed an unusual pattern, with preferential usage of distal TRAV and TRAJ segments. The TCR-beta (TRB) locus did not show abnormal gene rearrangement patterns. The findings suggested a founder effect for this geographical region.


See Also:

Acuto and Reinherz (1985); Baer et al. (1986); Caccia et al. (1985); Collins et al. (1985); Dembic et al. (1985); Epplen et al. (1987); Hedrick et al. (1984); Ibberson et al. (1995); Mak et al. (1987); Mathieu-Mahul et al. (1986); Minden et al. (1985); Sim et al. (1984); Yanagi et al. (1985); Yoshikai et al. (1985)

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Contributors:
Cassandra L. Kniffin - updated : 11/17/2021
Ada Hamosh - updated : 3/28/2014
Paul J. Converse - updated : 11/6/2013
Matthew B. Gross - updated : 9/30/2013
Paul J. Converse - updated : 9/30/2013
Cassandra L. Kniffin - updated : 8/29/2013
Ada Hamosh - updated : 9/21/2011
Paul J. Converse - updated : 7/31/2002
Paul J. Converse - updated : 8/18/2000
George E. Tiller - updated : 5/2/2000
Ada Hamosh - updated : 5/13/1999

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

Edit History:
carol : 11/22/2021
alopez : 11/19/2021
ckniffin : 11/17/2021
carol : 08/14/2020
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carol : 12/30/2015
alopez : 3/28/2014
mgross : 11/12/2013
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terry : 8/8/2012
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carol : 12/17/2009
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terry : 5/11/2009
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mgross : 8/21/2000
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alopez : 5/2/2000
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terry : 5/13/1999
dkim : 12/15/1998
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mark : 8/15/1997
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mimadm : 5/10/1995
warfield : 3/31/1994
carol : 3/14/1994
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carol : 11/17/1993



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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.
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