Alternative titles; symbols
HGNC Approved Gene Symbol: PTCRA
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38) : 6:42,916,053-42,925,838 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | Immunodeficiency 126 | 620931 | Autosomal recessive | 3 |
In immature T cells the T-cell receptor beta-chain (TCRB; see 186930) is rearranged and expressed before the TCRA (see 186880) chain. At this early stage, TCRB can associate with the pre-T-cell receptor alpha chain (PTCRA). The PTCRA, together with TCRB and the CD3 complex (see 186740), minimally make up the pre-T cell receptor (pre-TCR), which regulates early T cell development.
Using a cDNA corresponding to mouse Ptcra as a probe to screen a human thymus cDNA library, followed by 5- and 3-prime RACE, Del Porto et al. (1995) isolated a cDNA encoding a protein they named PTA for 'pre-T-cell receptor alpha chain.' The deduced 282-amino acid type I transmembrane protein, 63% identical to the mouse protein, contains a leader sequence, an Ig constant domain-like extracellular region with a potential N-glycosylation site, a transmembrane region, and a 114-amino acid cytoplasmic tail with 3 potential phosphorylation sites. The tail is much longer than that in the mouse protein. Southern blot analysis suggested the presence of a similar sequence in all species examined, but the cytoplasmic tail region appears to be restricted to primates. RT-PCR analysis detected expression in immature, but not mature, thymocyte subsets with strongest expression in CD4+/CD8-/CD3-low cells on their way to differentiate into CD4/CD8 double-positive thymocytes.
Materna et al. (2024) noted that the PTCRA gene encodes 2 functional isoforms: isoform A and isoform B, which is 106 amino acids shorter than isoform A and lacks part of the extracellular domain. RNA-seq analysis of thymocytes from 3 healthy control individuals indicated that isoform A is the principle isoform in human thymocytes. In addition to low levels of isoform B, 3 additional alternative transcripts were also identified at low levels.
By analysis of a chromosome 6 cosmid library, Saint-Ruf et al. (1998) determined that the PTCRA gene contains 4 exons with a first intron rich in repetitive Alu sequences and SINE and LINE elements. Analysis of the region 1.5 kb upstream of the ATG start codon detected no CAAT or TATA boxes or a potential promoter. However, the conserved 6.5-kb intron 1 contains binding sites for AP1 (165160) and for mu-EBP-C2. RT-PCR analysis identified a smaller splice variant, PT-alpha-2, encoding a 231-amino acid protein lacking a major part of the Ig-like domain, due to the elimination of exon 2. The variant lacks a potential N-glycosylation site but retains a number of potential O-glycosylation sites.
By radiolabeled in situ hybridization analysis, Del Porto et al. (1995) mapped the PTCRA gene to chromosome 6p21.2-p12. The authors noted that the mouse gene is localized to chromosome 17, also in the area of the major histocompatibility complex. Saint-Ruf et al. (1998) refined the localization to 6p21.3 by Southern blot and genomic sequence analysis.
In 10 individuals from 7 unrelated families, 3 of which were consanguineous, with susceptibility to immunodeficiency-126 (IMD126; 620931), Materna et al. (2024) identified biallelic loss-of-function mutations in the PTCRA gene (see, e.g., 606817.0001-606817.0003). The variants, which were found by exome or genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, but showed incomplete penetrance. Only 4 biallelic mutation carriers had clinical manifestations. Six others were clinically asymptomatic, including 4 who were identified through newborn SCID screening as having decreased T-cell receptor excision circles (TRECs). No PTCRA protein was detected in HEK293 cells transfected with the mutations, indicating that they likely triggered mRNA decay, and none were able to restore expression of TCR-beta or CD3 at the cell surface in vitro, indicating that they are loss-of-function alleles. None was present in the homozygous state in gnomAD.
Materna et al. (2024) found 15 biallelic missense variants in the PTCRA gene in public databases. Only 2 of these (D51A, 606817.0004 and Y76C), both of which affect residues interacting with TCR-beta (see 186930), were demonstrated to be functionally hypomorphic in in vitro studies. In gnomAD (v2.1.1), the Y76C variant was most frequent in sub-Saharan Africans, with a mean allele frequency of 0.0037 compared to 0.0003 in the global population. Materna et al. (2024) stated that in various databases D51A was most frequent in individuals from South Asia and the Middle East, with an MAF of 0.01, compared to 0.002 in the global population; this frequency indicates that D51A can be regarded as a 'common polymorphism.' About 1 in 4,000 individuals from the Middle East and South Asia were homozygous for the D51A variant. Homozygosity for D51A appeared to be a risk factor for autoimmunity, particularly hypothyroidism, conferring an odds ration (OR) of 5.02 compared to heterozygotes and homozygous wildtype individuals. Homozygous individuals did not show lymphoproliferation or unusual susceptibility to infection. D51A homozygotes had high circulating naive gamma/delta T cell counts and a significantly higher incidence of autoimmune disorders compared to the general population. Three individuals homozygous for the D51A hypomorphic variant (P11, P12, and P13), had low TREC levels and a high proportion of gamma/delta T cells among the naive T cell population. The D51A variant induced only very low levels of TCR-beta and CD3 expression in vitro, indicating that it is a hypomorphic allele.
By expressing Ptcra mutants in transgenic mice and in cell lines, Aifantis et al. (2002) showed that the conserved juxtamembrane cysteine that could be a target for palmitoylation appears to be dispensable for pre-TCR function. The nonconserved mouse cytoplasmic region, particularly its somewhat conserved proline-rich domain, is required for effective selection, proliferation, and survival of Tcrb-expressing immature thymocytes.
Materna et al. (2024) found that Ptcra-null mice had decreased numbers of CD4+ and CD8+ alpha/beta T cells that increased with age due to accumulation of memory T cells and increased gamma/delta T cells, similar to PTCRA-deficient humans.
In a 31-year-old Belgian woman (P3, family B) with immunodeficiency-126 (IMD126; 620931), Materna et al. (2024) identified a homozygous c.446G-A transition (c.446G-A, ENST00000304672) in the PTCRA gene, resulting in a trp149-to-ter (W149X) substitution in the transmembrane domain. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Exome sequencing also identified 2 Belgian sibs (P7 and P8, family E) with variable manifestations of IMD126 who were compound heterozygous for W149X and a 1-bp deletion (c.429delA; 606817.0002), predicted to result in a frameshift and premature termination (Pro144ArgfsTer24) in the extracellular domain. The parents in family E were deceased and could not be genotyped, but 2 unaffected sibs were heterozygous for 1 of the mutations. No PTCRA protein was detected in HEK293 cells transfected with either mutation, indicating that they likely triggered mRNA decay, and neither was able to restore expression of TCR-beta or CD3 at the cell surface in vitro, indicating that both are loss-of-function alleles. Materna et al. (2024) postulated a founder effect for the W149X mutation. The patients had variable manifestations. P3 had recurrent lower and upper respiratory infections since childhood and was diagnosed with CVID at 13 years of age. Additional immunologic features included adenopathies with lymphoproliferation, progressive thrombocytopenia, keratoconjunctivitis, and erosive duodenitis that responded to rituximab, suggesting an autoimmune origin. P3 also had syndromic features and intellectual disability with autism, most likely due to a de novo pathogenic nonsense mutation in the USP9X gene (300072). P7 was a 67-year-old woman with a recent history of recurrent respiratory infections and recurrent HSV1 episodes since age 25. She had panhypogammaglobulinemia with no detectable memory B cells, gradual pancytopenia, and autoantibodies to type 1 interferon; she was diagnosed with CVID as an adult. Other features included adult-onset hyperthyroidism, alopecia universalis with tooth loss, and thoracic non-Hodgkin B-cell lymphoma. Her 65-year-old brother (P8), who carried both mutations, was asymptomatic. Another brother died of cardiac arrest at age 50; he had alopecia universalis and hypothyroidism, but was not genotyped.
Hamosh (2024) noted that the W149X mutation was present in the gnomAD database (v4.1.0) in 17 of 1,590,668 alleles (allele frequency of 1.1 x 10(-5)), and the Pro144ArgfsTer24 mutation in 97 of 1,587,922 alleles (6.1 x 10(-5)). Both mutations were present in heterozygosity only.
For discussion of the 1-bp deletion (c.429delA, ENST00000304672) in the PTCRA gene, predicted to result in a frameshift and premature termination (Pro144ArgfsTer24), that was found in compound heterozygous state in 2 sibs with susceptibility to immunodeficiency-126 (IMD126; 620931) by Materna et al. (2024), see 606817.0001.
In 3 patients (P4, P5, and P6) from 2 unrelated consanguineous Iranian families (families C and D) with susceptibility to immunodeficiency-126 (IMD126; 620931), Materna et al. (2024) identified a homozygous 4-bp deletion (c.296_299del, ENST00000304672), predicted to result in a frameshift and premature termination (Leu99HisfsTer68) in the extracellular domain. The mutation was present in the heterozygous state in all 4 unaffected parents and an unaffected sib in family C. No PTCRA protein was detected in HEK293 cells transfected with the mutation, indicating that it likely triggered mRNA decay, and it was unable to restore expression of TCR-beta or CD3 at the cell surface in vitro, indicating that it is a loss-of-function allele. The mutation was not present in gnomAD (v4.1.0). The patients had variable manifestations. P4 (family C) was diagnosed with CVID at 17 years of age and died of SARS-CoV-2 at age 27. He had recurrent sinopulmonary infections with clubbing of the fingers and bronchiectasis, as well as hepatosplenomegaly, lymphadenopathy, thrombocytopenia, hypogammaglobulinemia, and impaired antibody response to vaccination. P5 (family D) was a 13-year-old girl who presented with a 3-month history of limb muscle weakness and difficulty walking associated with a peripheral sensorimotor demyelinating polyneuropathy suspected to be postinfectious Guillain-Barre syndrome. She also had autoimmune hypothyroidism with documented autoantibodies. Her brother (P6), who was also homozygous for the mutation, was healthy and asymptomatic, but had a history of nonspecific infectious episodes.
Materna et al. (2024) identified a common hypomorphic PTCRA polymorphism: c.152A-C (c.152A-C, ENST00000304672), resulting in an asp51-to-ala (D51A) substitution in the extracellular domain important for the interaction between PTCRA and TCR-beta. About 1 in 4,000 individuals from the Middle East and South Asia were predicted to be homozygous for the D51A variant. Homozygosity for D51A appeared to be a risk factor for autoimmunity, particularly hypothyroidism, conferring an odds ratio (OR) of 5.02 compared to heterozygotes and homozygous wildtype individuals. Homozygous individuals did not show lymphoproliferation or unusual susceptibility to infection. D51A homozygotes had high circulating naive gamma/delta T cell counts and a significantly higher incidence of autoimmune disorders compared to the general population. Three individuals homozygous for the D51A hypomorphic variant (P11, P12, and P13), had low TREC levels and a high proportion of gamma/delta T cells among the naive T cell population. The D51A variant induced only very low levels of TCR-beta and CD3 expression in vitro, indicating it is a hypomorphic allele.
Hamosh (2024) noted that the D51A variant in PTCRA was present in the gnomAD database (v4.1.0) at a frequency of 0.01675 in South Asians (1526 heterozygotes and 36 homozygotes among 91,090 alleles), compared to an overall frequency of 0.1, including the South Asian population.
Aifantis, I., Borowski, C., Gounari, F., Lacorazza, H. D., Nikolich-Zugich, J., von Boehmer, H. A critical role for the cytoplasmic tail of pT-alpha in T lymphocyte development. Nature Immun. 3: 483-488, 2002. Note: Erratum: Nature Immun. 3: 591 only, 2002. [PubMed: 11927911] [Full Text: https://doi.org/10.1038/ni779]
Del Porto, P., Bruno, L., Mattei, M.-G., von Boehmer, H., Saint-Ruf, C. Cloning and comparative analysis of the human pre-T-cell receptor alpha-chain gene. Proc. Nat. Acad. Sci. 92: 12105-12109, 1995. [PubMed: 8618853] [Full Text: https://doi.org/10.1073/pnas.92.26.12105]
Hamosh, A. Personal Communication. Baltimore, Md. 09/04/2024.
Materna, M., Delmonte, O. M., Bosticardo, M., Momenilandi, M., Conrey, P. E., Charmeteau-De Muylder, B., Bravetti, C., Bellworthy, R., Cederholm, A., Staels, F., Ganoza, C. A., Darko, S., and 87 others. The immunopathological landscape of human pre-TCR-alpha deficiency: from rare to common variants. Science 383: eadh4059, 2024. [PubMed: 38422122] [Full Text: https://doi.org/10.1126/science.adh4059]
Saint-Ruf, C., Lechner, O., Feinberg, J., von Boehmer, H. Genomic structure of the human pre-T cell receptor alpha chain and expression of two mRNA isoforms. Europ. J. Immun. 28: 3824-3831, 1998. [PubMed: 9842925] [Full Text: https://doi.org/10.1002/(SICI)1521-4141(199811)28:11<3824::AID-IMMU3824>3.0.CO;2-9]