Alternative titles; symbols
HGNC Approved Gene Symbol: LCP2
Cytogenetic location: 5q35.1 Genomic coordinates (GRCh38): 5:170,246,233-170,297,777 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.1 | Immunodeficiency 81 | 619374 | Autosomal recessive | 3 |
The LCP2 gene encodes a key adaptor molecule involved in intracellular signaling. It has a particular role within the downstream signaling cascade in T lymphocytes that is initiated by activation of the T-cell receptor (TCR). This process ultimately leads to a fully activated T cell through calcium mobilization and reorganization of the actin cytoskeleton (summary by Lev et al., 2021).
Activation of tyrosine kinases of the src and syk family is required for T-cell receptor-mediated signaling. Jackman et al. (1995) identified a 76-kD protein that associates with the Grb2 adaptor protein (108355) and is a substrate for tyrosine kinase in the activation pathway. The SLP76 (SH2 domain-containing leukocyte protein of 76 kD) cDNA encodes a predicted 533-amino acid protein with a single C-terminal Src homology 2 (SH2) domain, a proline-rich region with a binding site for Grb2, and an acidic N-terminal region with tyrosines that are phosphorylated after T-cell receptor engagement (Sunden et al., 1996). The human and mouse amino acid sequences are 84% identical. Northern blots demonstrated expression in peripheral blood leukocytes, thymus, and spleen and in human T-cell, B-cell, and monocytic cell lines. Recombinantly expressed SLP76 was shown to associate with a GST/Grb2 fusion protein. Overexpression of SLP76 has also been shown to enhance the activity of the promoter for the IL2 gene (Motto et al., 1996).
Sunden et al. (1996) used a monochromosomal somatic cell hybrid panel to map the LCP2 gene to chromosome 5. They then used a 2-allele polymorphism within the gene to map the locus genetically near the marker D5S429, which has been assigned to 5q33.1-qter.
In a male infant, born of consanguineous Palestinian parents, with immunodeficiency-81 (IMD81; 619374), Lev et al. (2021) identified a homozygous splice site mutation in the LCP2 gene (601603.0001) resulting in a hypomorphic allele. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Immunologic workup showed increased CD8 T cells and a low proportion of CD4 T cells. Residual CD4 T cells were skewed toward a central memory phenotype, and CD8 T cells were consistent with a terminally differentiated T-effector memory RA (TEMRA) phenotype. Peripheral T lymphocyte proliferation was impaired in response to PHA and anti-CD3; this defect responded partially to treatment with IL2 (147680). CD4 T cells had decreased production of cytokines, including gamma-interferon (IFNG; 147570), but CD8 T cells produced high levels of IFNG. T-cell receptor (TCR) extension circles (TRECs) were decreased, suggesting low thymic activity, and the TCR repertoire was decreased. Patient T cells had complete absence of calcium mobilization and failed to secrete cytokines after stimulation with anti-CD3, suggesting a defect in intracellular signaling pathways downstream of the TCR. B cell numbers were normal, but there were reduced class-switched memory B cells and increased naive or immature B cells, suggesting a defect in B-cell receptor signaling. NK cells were also normal in number, but showed impaired degranulation that could partially be rescued by expression of IL2. Patient neutrophils were dysfunctional, showing impaired responses, decreased superoxide production and bacterial killing, and decreased chemotaxis compared to controls, which was consistent with fungal infections in the patient. Although platelet count was normal, the patient's platelets showed reduced aggregation, specifically in response to collagen. Patient fibroblasts showed impaired cytoskeletal assembly, suggesting reduced actin polymerization. Transduction of patient primary T lymphocytes with wildtype LCP2 partially rescued CD69 (107273) expression and partially rescued defects in calcium mobilization. The authors noted the similarities to studies of mice with loss of Lcp2 (see ANIMAL MODEL).
In a 4-year-old boy, born of consanguineous Muslim parents, with IMD81, Lev et al. (2023) identified a homozygous frameshift mutation in the LCP2 gene (601603.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into an LCP2-null Jurkat T-cell line resulted in reduced signaling downstream of the TCR, including decreased ERK1/2 (see 176948) phosphorylation and decreased CD69 (107273) surface expression. TCR-induced calcium mobilization was also decreased compared to wildtype, consistent with impaired T-cell activation. In addition to recurrent infections, the patient developed EBV-associated diffuse large B-cell lymphoma and died at 4 years of age.
In a 26-year-old man, born of unrelated Vietnamese parents, with IMD81, Edwards et al. (2023) identified compound heterozygous missense mutations in the LCP2 gene (P190R, 601603.0003 and R204W, 601603.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing; familial segregation studies could not be performed. Both mutations occurred at conserved residues within the proline-rich repeat domain. The SLP76 protein was decreased in patient T and NK cells, and undetectable in B cells, suggesting that the LCP2 mutations caused accelerated protein decay. Patient T and B cells showed impaired signal transduction after antigen-receptor engagement, with T cells showing absent phosphorylation of downstream signaling molecules, and B cells showing severely reduced downstream phosphorylation. Similar results were obtained after transfection of the mutations into LCP2-null Jurkat T cells, although the results suggested that there could be some residual function. Edwards et al. (2023) postulated that the immune dysregulation in the patient could be due to partial BCR/TCR signaling that impairs regulatory T-cell function and affects positive and negative immune cell selection, resulting in autoimmunity. Importantly, the authors noted that since the LCP2 mutations affected signaling through PI3K (see 171834), treatment with sirolimus, an inhibitor of PI3K signaling, was ineffective in the patient.
The adaptor protein SLP76 is expressed in T lymphocytes and myeloid cells and is a substrate for ZAP70 (176947) and SYK (600085). Pivniouk et al. (1998) generated a SLP76 null mutation in mice by homologous recombination in embryonic stem cells to evaluate the role of SLP76 in T-cell development and activation. SLP76-deficient mice exhibited subcutaneous and intraperitoneal hemorrhaging and impaired viability. Analysis of lymphoid cells revealed a profound block in thymic development with absence of double-positive CD4+8+ thymocytes and of peripheral T cells. This block could not be rescued by in vivo treatment with anti-CD3. V-D-J rearrangement of the TCR-beta locus was not obviously affected. B-cell development was normal. These results indicated that SLP76 collects all pre-TCR signals that drive the development and expansion of double-positive thymocytes.
Clements et al. (1999) described fetal hemorrhage and perinatal mortality in mice deficient in SLP76. Although megakaryocyte and platelet development proceeded normally in the absence of SLP76, collagen-induced platelet aggregation and granule release were markedly impaired. Furthermore, treatment of SLP76-deficient platelets with collagen failed to elicit tyrosine phosphorylation of phospholipase C-gamma-2, suggesting that SLP76 functions upstream of PLC-gamma-2 activation. The data provided a potential mechanism for the fetal hemorrhage observed in the SLP76-deficient mice and showed that SLP76 expression is required for optimal receptor-mediated signal transduction in platelets as well as in T lymphocytes.
Abtahian et al. (2003) identified a failure to separate emerging lymphatic vessels from blood vessels in mice lacking the hematopoietic signaling protein Slp76 or Syk. Blood-lymphatic connections led to embryonic hemorrhage and arteriovenous shunting. Expression of Slp76 could not be detected in endothelial cells, and blood-filled lymphatics also arose in wildtype mice reconstituted with Slp76-deficient bone marrow. Abtahian et al. (2003) concluded that their studies revealed a hematopoietic signaling pathway required for separation of the 2 major vascular networks in mammals. Absence of Slp76 usually results in embryonic hemorrhage and perinatal death in addition to loss of immune receptor signaling. However, Abtahian et al. (2003) observed that Slp76-deficient mice that survived to adulthood had cardiomegaly by 12 weeks of age due to elevated cardiac output. Slp76-deficient animals were not anemic, and analysis of Slp76-deficient hearts revealed no structural cardiac abnormalities. Examination of the peripheral vasculature in Slp76-deficient mice revealed a network of dilated and tortuous blood vessels throughout the small intestine, which were shown to mediate arteriovenous shunting of blood. A cutaneous hemorrhagic appearance, first noted at midgestation, is the most striking phenotype observed in mouse embryos lacking Syk, Slp76, or PLC-gamma-2 (600220). Abtahian et al. (2003) noted that the pattern and timing of this phenotype closely resembled that of developing cutaneous lymphatics first described by Sabin (1901). Histologic analysis of the skin of Slp76-deficient embryos revealed that most of the blood observed was not extravasated hemorrhage but instead was contained within thin-walled vessels that stained weakly for the endothelial marker CD31 (173445) and not at all for smooth muscle actin (see 102540), features consistent with lymphatic vessels.
Kumar et al. (2005) reconstituted Slp76 -/- mice with Slp76 lacking the LCK (153390)-binding region (amino acids 185 to 194). The reconstituted mice had altered thymocyte populations with impaired positive selection and increased apoptosis, as well as reduced peripheral T-cell numbers. The T cells, in turn, manifested impaired in vitro and in vivo function. Kumar et al. (2005) concluded that the LCK-binding region of SLP76 is essential for T-cell antigen receptor signaling and normal T-cell development and function.
In a male infant, born of consanguineous Palestinian parents, with immunodeficiency-81 (IMD81; 619374), Lev et al. (2021) identified a homozygous G-to-A transition in intron 14 of the LCP2 gene (c.957+1G-A), resulting in the skipping of exon 14, a frameshift, and premature termination (Lys309fsTer17). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot and flow cytometric analysis of patient cells showed complete loss of LCP2 expression, although an unstable truncated protein was detected in Jurkat-derived cells transfected with the mutation. The mutation occurred in the central proline-rich domain and was predicted to result in deletion of the C-terminal SH2 domain. The authors postulated a hypomorphic effect.
In a 4-year-old boy, born of consanguineous Muslim parents, with immunodeficiency-81 (IMD81; 619374), Lev et al. (2023) identified a homozygous 1-bp deletion (c.991delC) in exon 16 of the LCP2 gene, resulting in a frameshift and premature termination (Gln331SerfsTer6) at the end of the proline-rich domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. disorder in the family. Transfection of the mutation into an LCP2-null Jurkat T-cell line resulted in reduced signaling downstream of the TCR, including decreased ERK1/2 (see 176948) phosphorylation and decreased CD69 (107273) surface expression. TCR-induced calcium mobilization was also decreased compared to wildtype, consistent with impaired T-cell activation. In addition to recurrent infections, the patient developed EBV-associated diffuse large B-cell lymphoma and died at 4 years of age.
In a 26-year-old man, born of unrelated Vietnamese parents, with immunodeficiency-81 (IMD81; 619374), Edwards et al. (2023) identified compound heterozygous missense mutations in the LP2 gene: a c.569C-G transversion, resulting in a pro190-to-arg (P190R) and a c.610C-T transition, resulting in an arg204-to-trp (R204W; 601603.0004) substitution. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing; familial segregation studies could not be performed. Both mutations occurred at conserved residues within the proline-rich repeat domain. The SLP76 protein was decreased in patient T and NK cells, and undetectable in B cells, suggesting that the LCP2 mutations caused accelerated protein decay. Patient T and B cells showed impaired signal transduction after antigen-receptor engagement, with T cells showing absent phosphorylation of downstream signaling molecules, and B cells showing severely reduced downstream phosphorylation. Similar results were obtained after transfection of the mutations into LCP2-null Jurkat T cells in vitro, although the results suggested that there could be some residual function.
For discussion of the c.610C-T transition in the LCP2 gene, resulting in an arg204-to-trp (R204W) substitution, that was found in compound heterozygous state in a patient with immunodeficiency-81 (IMD81; 619374) by Edwards et al. (2023), see 601603.0003.
Abtahian, F., Guerriero, A., Sebzda, E., Lu, M.-M., Zhou, R., Mocsai, A., Myers, E. E., Huang, B., Jackson, D. G., Ferrari, V. A., Tybulewicz, V., Lowell, C. A., Lepore, J. J., Koretzky, G. A., Kahn, M. L. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299: 247-251, 2003. [PubMed: 12522250] [Full Text: https://doi.org/10.1126/science.1079477]
Clements, J. L., Lee, J. R., Gross, B., Yang, B., Olson, J. D., Sandra, A., Watson, S. P., Lentz, S. R., Koretzky, G. A. Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice. J. Clin. Invest. 103: 19-25, 1999. [PubMed: 9884330] [Full Text: https://doi.org/10.1172/JCI5317]
Edwards, E. S. J., Ojaimi, S., Ngui, J., Seo, G. H., Kim, J., Chunilal, S., Yablonski, D., O'Hehir, R. E., van Zelm, M. C. Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants. J. Allergy Clin. Immun. 152: 807-813, 2023. [PubMed: 37211057] [Full Text: https://doi.org/10.1016/j.jaci.2023.04.020]
Jackman, J. K., Motto, D. G., Sun, Q., Tanemoto, M., Turck, C. W., Peltz, G. A., Koretzky, G. A., Findell, P. R. Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotein associated with Grb2 in T cells. J. Biol. Chem. 270: 7029-7032, 1995. [PubMed: 7706237] [Full Text: https://doi.org/10.1074/jbc.270.13.7029]
Kumar, L., Feske, S., Rao, A., Geha, R. S. A 10-aa-long sequence in SLP-76 upstream of the Gads binding site is essential for T cell development and function. Proc. Nat. Acad. Sci. 102: 19063-19068, 2005. [PubMed: 16354835] [Full Text: https://doi.org/10.1073/pnas.0509176102]
Lev, A., Asleh, M., Levy, S., Lee, Y. N., Simon, A. J., Stepensky, P., Nalbandyan, K., Nahum, A., Ben-Harosh, M., Yablonski, D., Broides, A., Somech, R. SLP76 mutation associated with combined immunodeficiency and EBV-related lymphoma. J. Clin. Immun. 43: 625-635, 2023. [PubMed: 36474126] [Full Text: https://doi.org/10.1007/s10875-022-01412-4]
Lev, A., Lee, Y. N., Sun, G., Hallumi, E., Simon, A. J., Zrihen, K. S., Levy, S., Beit Halevi, T., Papazian, M., Shwartz, N., Somekh, I., Levy-Mendelovich, S., and 14 others. Inherited SLP76 deficiency in humans causes severe combined immunodeficiency, neutrophil and platelet defects. J. Exp. Med. 218: e20201062, 2021. [PubMed: 33231617] [Full Text: https://doi.org/10.1084/jem.20201062]
Motto, D. G., Ross, S. E., Wu, J., Hendricks-Taylor, L. R., Koretzky, G. A. Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production. J. Exp. Med. 183: 1937-1943, 1996. [PubMed: 8666952] [Full Text: https://doi.org/10.1084/jem.183.4.1937]
Pivniouk, V., Tsitsikov, E., Swinton, P., Rathbun, G., Alt, F. W., Geha, R. S. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 94: 229-238, 1998. [PubMed: 9695951] [Full Text: https://doi.org/10.1016/s0092-8674(00)81422-1]
Sabin, F. R. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am. J. Anat. I: 367-389, 1901.
Sunden, S. L. F., Carr, L. L., Clements, J. L., Motto, D. G., Koretzky, G. A. Polymorphism in and localization of the gene LCP2 (SLP-76) to chromosome 5q33.1-qter. Genomics 35: 269-270, 1996. [PubMed: 8661136] [Full Text: https://doi.org/10.1006/geno.1996.0354]