* 176947

ZETA-CHAIN-ASSOCIATED PROTEIN KINASE; ZAP70


Alternative titles; symbols

SYK-RELATED TYROSINE KINASE; SRK
PROTEIN TYROSINE KINASE ZAP70
ZETA-ASSOCIATED PROTEIN, 70-KD


HGNC Approved Gene Symbol: ZAP70

Cytogenetic location: 2q11.2     Genomic coordinates (GRCh38): 2:97,713,576-97,756,364 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q11.2 Autoimmune disease, multisystem, infantile-onset, 2 617006 AR 3
Immunodeficiency 48 269840 AR 3

TEXT

Description

The ZAP70 gene encodes a tyrosine kinase that is a critical T-cell signaling molecule that interacts with the zeta-chain (CD247; 186780) of the T-cell receptor (TCR). It is expressed predominantly in T and NK cells (summary by Chan et al., 2016).


Cloning and Expression

Chan et al. (1992) isolated a cDNA encoding a 70-kD tyrosine phosphoprotein, ZAP70, that associates with the zeta chain and undergoes tyrosine phosphorylation following TCR stimulation. The ZAP70 gene is expressed in T- and natural killer cells.


Mapping

Chan et al. (1994) mapped the ZAP70 gene to chromosome 2q12 by hybridization of a genomic fragment to human/rodent somatic hybrid cell DNA and by fluorescence in situ hybridization (FISH). Ku et al. (1994) likewise assigned the ZAP70 gene to 2q12 by isotopic in situ hybridization. They mapped the murine homolog to mouse chromosome 1 by the same method. Saito et al. (1997) also mapped the gene to mouse chromosome 1 and rat chromosome 9q22.1 by FISH; by genetic linkage analysis, they further refined the location of the gene on mouse chromosome 1.


Gene Function

Watts et al. (1996) identified a ZAP70 phosphorylation site on the erythrocyte band-3 protein (see 109270) cytoplasmic fragment. They found that this phosphorylation site is distinct from the phosphorylation sites for other PTKs.

Animals deficient in pre-TCR-alpha have few alpha-beta lineage cells but an increased number of gamma-delta T cells. These gamma-delta T cells exhibit more extensive TCR-beta rearrangement than gamma-delta T cells from wildtype mice. These observations are consistent with the idea that different signals emanating from the gamma-delta-TCR and pre-TCR instruct lineage commitment. Using confocal microscopy and biochemistry to analyze the initiation of signaling, Saint-Ruf et al. (2000) showed that the pre-TCR, but not the gamma-delta TCR, colocalizes with the p56(lck) Src kinase (153390) into glycolipid-enriched membrane domains (rafts) apparently without any need for ligation. This results in the phosphorylation of CD3-epsilon (186830) and ZAP70 signal transducing molecules. Saint-Ruf et al. (2000) stated that their results indicated clear differences between pre-TCR and gamma-delta-TCR signaling.

Colucci et al. (2002) noted that humans with mutations in ZAP70 have T-cell immunodeficiency, that mice lacking Zap70 have blocked T-cell development, and that mice lacking Syk (600085) have a failure of B-cell development. NK cells express both molecules, which associate with immunoreceptor tyrosine-based activation motifs (ITAMs). Using mice deficient in both Zap70 and Syk, Colucci et al. (2002) observed NK cell activity comparable to that in wildtype mice. The mutant cells expressed Nkg2d (602893) and were able to lyse targets with and without Nkg2d ligands in vitro and in vivo. However, wildtype cells, but not the double-deficient cells, responded to CD16 (146740) and Ly49d (see 604274) cross-linking with increased cytotoxicity, suggesting that these 2 ITAM-bearing receptors are unable to signal in the mutant cells. Inhibitors of PI3K (see 601232) or Src kinases blocked and, in combination, abrogated cytotoxic activity in the mutant cells, whereas inhibition of both kinases was required to reduce wildtype NK activity. Colucci et al. (2002) concluded that intracellular signaling in the adaptive immune system, i.e., in B and T cells, is fundamentally different from that in the NK cells of the innate immune system.

Sasahara et al. (2002) showed that the adaptor protein CRKL (602007) binds directly to WIP (602357) and that, following T-cell receptor ligation, a CRKL-WIP-WASP (300392) complex is recruited by ZAP70 to lipid rafts and immunologic synapses.

Crespo et al. (2003) found that ZAP70 expression by cells in chronic lymphocytic leukemia (CLL; 151400), as ascertained by flow cytometric analysis, is a simple and reliable surrogate for the identification of immunoglobulin heavy chain variable region gene (IGHV; see 147070) mutations. Moreover, ZAP70 expression by itself can be used as a prognostic marker. For these reasons, they urged that ZAP70 analysis be included in the workup of patients with CLL.

Using in vitro binding assays, Gu et al. (2006) showed that Rhoh (602037) interacted with Zap70. The Rhoh-Zap70 interaction depended mainly on conserved tyrosine-phosphorylated ITAMs in Rhoh and the SH2 domains in Zap70. Rhoh was required for proper recruitment of Zap70 to plasma membrane and cytoskeleton fractions in thymocytes and consequently for activation of Zap70 in TCR signal transduction. Based on these findings and studies in Rhoh -/- mice, Gu et al. (2006) concluded that RHOH is a critical regulator of thymocyte development and TCR signaling via its recruitment and activation of ZAP70.


Molecular Genetics

Immunodeficiency 48

In 3 affected females from 2 Mennonite families with immunodeficiency-48 (IMD48; 269840) characterized by a selective T-cell defect, Arpaia et al. (1994) identified a homozygous mutation in the ZAP70 (176947.0001), resulting in loss of the activity of this kinase. The mutation was present in heterozygous state in the parents and 3 unaffected sibs.

In 3 sibs, 2 boys and a girl, with IMD48, Chan et al. (1994) identified compound heterozygous mutations in the ZAP70 gene (176947.0002 and 176947.0003).

In a female infant with IMD48, Elder et al. (1994) identified a homozygous mutation in the ZAP70 gene (176947.0004). The parents and unaffected sibs were heterozygous for the mutation.

Chronic Lymphocytic Leukemia

Rassenti et al. (2004) noted that in cases of aggressive chronic lymphocytic leukemia (151400), CLL cells usually express an unmutated immunoglobulin heavy chain variable region gene (IGHV; see 147070) and ZAP70 gene, whereas in cases of indolent disease, CLL cells usually express a mutated immunoglobulin heavy chain variable region gene but lack expression of ZAP70. In studies of 307 patients with CLL, Rassenti et al. (2004) found that although the presence of an unmutated immunoglobulin heavy chain variable region gene was strongly associated with expression of ZAP70, ZAP70 was a stronger predictor of the need for treatment in B-cell CLL.

Infantile-Onset Multisystem Autoimmune Disease 2

In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006), Chan et al. (2016) identified compound heterozygous missense mutations in the ZAP70 gene (R192W, 176947.0006 and R360P, 176947.0007). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Studies of transfected cell lines and cells from the carrier parents showed that the R192W was a hypomorphic allele with reduced binding to phosphorylated zeta-chain (CD247; 186780) of the TCR, whereas R360P was weakly hyperactive compared to wildtype, most likely due to disruption of the autoinhibitory mechanism. The combination of hypomorphic and activating mutations suggested a novel disease mechanism resulting in a theretofore undescribed human ZAP70-associated autoimmune disease.


Animal Model

Sakaguchi et al. (2003) reported that the SKG strain, which is derived from a closed breeding colony of BALB/c mice, spontaneously develops chronic arthritis. Joint swelling with hyperemia became macroscopically evident in SKG mice at about 2 months of age, initially at a few interphalangeal joints of the forepaws, then progressing in a symmetrical fashion to swelling of the other finger joints of the forepaws and hindpaws and larger joints (wrists and ankles). Knee, elbow, shoulder, or vertebral joints were rarely affected except for the joint at the base of the tail in aged SKG mice. Radiographic examination revealed destruction and fusion of the subchondral bones, joint dislocation, and osteoporosis by 8 to 12 months of age. Despite suffering from such severe chronic arthritis, most SKG mice survived well to 1 year of age, generally with more severe arthritides in females. Sakaguchi et al. (2003) found that this arthritis is an autosomal recessive trait. They found a tryptophan-to-cysteine substitution at residue 163 (W163C) at the start of the second SH2 domain of ZAP70. Altered signal transduction from T-cell antigen receptor (see 186740) through the aberrant ZAP70 changes the threshold of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Sakaguchi et al. (2003) speculated that thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might be crucial to the development of disease in a subset of patients with rheumatoid arthritis.


ALLELIC VARIANTS ( 7 Selected Examples):

.0001 IMMUNODEFICIENCY 48

ZAP70, IVS, G-A, -11
  
RCV000014158...

In 3 females in 2 different families from a genetically isolated Mennonite community in Ontario, Arpaia et al. (1994) demonstrated that immunodeficiency-48 (IMD48; 269840) due to a selective T-cell defect was the result of homozygosity for a splice mutation in the ZAP70 gene. An intronic point mutation created a new splice acceptor site with the insertion of 9 nucleotides in the mRNA and 3 additional amino acids in the protein product. The G-to-A transition at position -11 from the 3-prime end of the intron created an AluI restriction site which Arpaia et al. (1994) used for identifying heterozygotes in the family. Both parents were carriers and 3 of 4 sibs were heterozygous as well. The mutation resulted in an unstable protein that could not be detected by Western blotting or kinase activity.


.0002 IMMUNODEFICIENCY 48

ZAP70, IVS, G-A, -9
   RCV000014158...

In 2 brothers and a sister with immunodeficiency-48 (IMD48; 269840), Chan et al. (1994) identified compound heterozygous mutations in the ZAP70 gene. One mutation, inherited from the mother, was a 9-bp insertion due to a G-to-A transition within an intron 9-bp upstream of the normal splice acceptor site. The mutation resulted in a more favored splice acceptor site (AGC rather than AGA) and in the addition of 3 amino acids, leu-glu-gln, within the catalytic domain of the ZAP70 protein. The other mutation, inherited from the father, was a 1763C-A transition resulting in a ser518-to-arg (S518R; 176947.0003) substitution. Ser518 is in a highly conserved region of the catalytic domain of the ZAP70 protein.


.0003 IMMUNODEFICIENCY 48

ZAP70, SER518ARG
  
RCV000033208

For discussion of the ser518-to-arg (S518R) mutation in the ZAP70 gene that was found in compound heterozygous state in patients with immunodeficiency-48 (IMD48; 269840) by Chan et al. (1994), see 176947.0002.


.0004 IMMUNODEFICIENCY 48

ZAP70, 13-BP DEL, NT1719
  
RCV000014164

In a 1-year-old female with immunodeficiency-48 (IMD48; 269840), Elder et al. (1994) demonstrated homozygosity for a 13-bp deletion involving nucleotides 1719-1731 (1719_1931del13) of the ZAP70 gene. The deletion would be expected to cause a translational frameshift after amino acid 503, resulting in premature termination 35 codons downstream and yielding a mutant protein 82 residues shorter than the wildtype. Both parents and 2 unaffected sibs were heterozygous for the mutation.


.0005 IMMUNODEFICIENCY 48

ZAP70, ARG465HIS
  
RCV000033214...

In an 8-month-old girl with immunodeficiency-48 (IMD48; 269840), Toyabe et al. (2001) detected a homozygous 1603G-A transition in the ZAP70 gene, resulting in an arg465-to-his substitution in the kinase domain. The patient lacked CD8-positive T cells but had normal CD4-positive T cells and serum Ig levels. ZAP70-deficient patients rarely have antigen-specific antibodies, but this patient developed specific IgE antibodies (see 147050) to food allergens without developing food allergies. Stimulation of peripheral blood mononuclear cells with phorbol myristate acetate, but not with other mitogens, resulted in production of high levels of IL4 (147780), T-cell expression of CD40L (300386), and expression of germline and mature IgE epsilon transcripts in B cells. Western blot analysis showed expression of high levels of SYK (600085) in T cells from the patient, which also expressed high levels of CD40L, but not in those from controls. A protein tyrosine kinase/SYK inhibitor aborted IL4 production and CD40L expression. Toyabe et al. (2001) proposed that partial T-cell function and a T-cell receptor-signaling pathway can be retained in some ZAP70-deficient patients via SYK.


.0006 AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)

ZAP70, ARG192TRP
  
RCV000208562...

In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006), Chan et al. (2016) identified compound heterozygous mutations in the ZAP70 gene: a c.574C-T transition (c.574C-T, NM_001079.3) in exon 5, resulting in an arg192-to-trp (R192W) substitution in the phosphotyrosine-binding pocket, and a c.1079G-C transversion in exon 9, resulting in an arg360-to-pro (R360P; 176947.0007) substitution in the N-lobe of the kinase domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Transfection of the mutations into HEK293 T cells showed that the R192W mutant had reduced association with phosphorylated zeta-chains, consistent with it being a hypomorphic allele. Transfection of the R360P mutant did not result in constitutive LAT phosphorylation, but nearby D327P and K362E mutants did cause increased activity, suggesting that all these mutations may interfere with proper autoinhibition of ZAP70. Further studies in another T-cell line indicated that the R360P mutant is weakly hyperactive due to disruption of its autoinhibitory mechanism. Patient cells were not available because both patients had undergone hematopoietic stem cell transplantation, but studies of cells from the heterozygous parents were consistent with R192W being a hypoactive mutant and R360P being weakly hyperactive. Finally, double-transfected cells showed that the R360P phenotype was masked by wildtype ZAP70 and revealed only in the presence of the hypoactive R192W allele.


.0007 AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)

ZAP70, ARG360PRO
  
RCV000208547...

For discussion of the c.1079G-C transversion (c.1079G-C, NM_001079.3) in exon 9 of the ZAP70 gene, resulting in an arg360-to-pro (R360P) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006) by Chan et al. (2016), see 176947.0006.


REFERENCES

  1. Arpaia, E., Shahar, M., Dadi, H., Cohen, A., Roifman, C. M. Defective T cell receptor signaling and CD8(+) thymic selection in humans lacking Zap-70 kinase. Cell 76: 947-958, 1994. [PubMed: 8124727, related citations] [Full Text]

  2. Chan, A. C., Iwashima, M., Turck, C. W., Weiss, A. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 71: 649-662, 1992. [PubMed: 1423621, related citations] [Full Text]

  3. Chan, A. C., Kadlecek, T. A., Elder, M. E., Filipovich, A. H., Kuo, W.-L., Iwashima, M., Parslow, T. G., Weiss, A. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264: 1599-1601, 1994. [PubMed: 8202713, related citations] [Full Text]

  4. Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M. A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J. Exp. Med. 213: 155-165, 2016. [PubMed: 26783323, images, related citations] [Full Text]

  5. Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J. R., Vivier, E., Tybulewicz, V. L. J., Di Santo, J. P. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nature Immun. 3: 288-294, 2002. [PubMed: 11836527, related citations] [Full Text]

  6. Crespo, M., Bosch, F., Villamor, N., Bellosillo, B., Colomer, D., Rozman, M., Marce, S., Lopez-Guillermo, A., Campo, E., Montserrat, E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. New Eng. J. Med. 348: 1764-1775, 2003. [PubMed: 12724482, related citations] [Full Text]

  7. Elder, M. E., Lin, D., Clever, J., Chan, A. C., Hope, T. J., Weiss, A., Parslow, T. G. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264: 1596-1599, 1994. [PubMed: 8202712, related citations] [Full Text]

  8. Gu, Y., Chae, H.-D., Siefring, J. E., Jasti, A. C., Hildeman, D. A., Williams, D. A. RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nature Immun. 7: 1182-1190, 2006. [PubMed: 17028588, related citations] [Full Text]

  9. Ku, G., Malissen, B., Mattei, M.-G. Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans. Immunogenetics 40: 300-302, 1994. [PubMed: 8082894, related citations] [Full Text]

  10. Rassenti, L. Z., Huynh, L., Toy, T. L., Chen, L., Keating, M. J., Gribben, J. G., Neuberg, D. S., Flinn, I. W., Rai, K. R., Byrd, J. C., Kay, N. E., Greaves, A., Weiss, A., Kipps, T. J. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. New Eng. J. Med. 351: 893-901, 2004. [PubMed: 15329427, related citations] [Full Text]

  11. Saint-Ruf, C., Panigada, M., Azogui, O., Debey, P., von Boehmer, H., Grassi, F. Different initiation of pre-TCR and gamma-delta-TCR signalling. Nature 406: 524-527, 2000. [PubMed: 10952314, related citations] [Full Text]

  12. Saito, T., Matsuda, Y., Ito, H., Fusaki, N., Hori, T., Yamamoto, T. Localization of Zap70, the gene for a T cell-specific protein tyrosine kinase, to mouse and rat chromosomes by fluorescence in situ hybridization and molecular genetic linkage analyses. Mammalian Genome 8: 45-46, 1997. [PubMed: 9021148, related citations] [Full Text]

  13. Sakaguchi, N., Takahashi, T., Hata, H., Nomura, T., Tagami, T., Yamazaki, S., Sakihama, T., Matsutani, T., Negishi, I., Nakatsuru, S., Sakaguchi, S. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426: 454-460, 2003. [PubMed: 14647385, related citations] [Full Text]

  14. Sasahara, Y., Rachid, R., Byrne, M. J., de la Fuente, M. A., Abraham, R. T., Ramesh, N., Geha, R. S. Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Molec. Cell 10: 1269-1281, 2002. [PubMed: 12504004, related citations] [Full Text]

  15. Toyabe, S.-I., Watanabe, A., Harada, W., Karasawa, T., Uchiyama, M. Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling. Immunology 103: 164-171, 2001. [PubMed: 11412303, images, related citations] [Full Text]

  16. Watts, J. D., Brabb, T., Bures, E. J., Wange, R. L., Samelson, L. E., Aebersold, R. Identification and characterization of a substrate specific for the T cell protein tyrosine kinase ZAP-70. FEBS Lett. 398: 217-222, 1996. [PubMed: 8977110, related citations] [Full Text]


Bao Lige - updated : 03/14/2019
Cassandra L. Kniffin - updated : 6/27/2016
Victor A. McKusick - updated : 9/13/2004
Ada Hamosh - updated : 12/1/2003
Victor A. McKusick - updated : 6/6/2003
Stylianos E. Antonarakis - updated : 4/28/2003
Paul J. Converse - updated : 2/11/2002
Paul J. Converse - updated : 7/17/2001
Ada Hamosh - updated : 8/2/2000
Jennifer P. Macke - updated : 5/27/1998
Victor A. McKusick - updated : 2/12/1997
Creation Date:
Victor A. McKusick : 12/3/1992
carol : 05/27/2020
carol : 03/18/2019
mgross : 03/14/2019
mgross : 03/14/2019
carol : 07/07/2016
alopez : 6/28/2016
ckniffin : 6/27/2016
carol : 2/10/2015
mcolton : 2/9/2015
mgross : 2/11/2014
mcolton : 1/23/2014
joanna : 12/14/2012
carol : 10/25/2012
tkritzer : 9/14/2004
terry : 9/13/2004
joanna : 3/17/2004
alopez : 12/2/2003
terry : 12/1/2003
tkritzer : 6/12/2003
tkritzer : 6/12/2003
tkritzer : 6/11/2003
terry : 6/6/2003
mgross : 4/28/2003
carol : 4/8/2002
alopez : 3/12/2002
alopez : 2/11/2002
alopez : 2/11/2002
alopez : 2/11/2002
mgross : 7/17/2001
mgross : 7/17/2001
alopez : 8/2/2000
carol : 8/18/1998
carol : 8/3/1998
dholmes : 5/27/1998
dholmes : 5/27/1998
dholmes : 4/16/1998
terry : 2/12/1997
terry : 2/7/1997
mimadm : 2/25/1995
carol : 1/27/1995
jason : 6/21/1994
carol : 12/3/1992

* 176947

ZETA-CHAIN-ASSOCIATED PROTEIN KINASE; ZAP70


Alternative titles; symbols

SYK-RELATED TYROSINE KINASE; SRK
PROTEIN TYROSINE KINASE ZAP70
ZETA-ASSOCIATED PROTEIN, 70-KD


HGNC Approved Gene Symbol: ZAP70

Cytogenetic location: 2q11.2     Genomic coordinates (GRCh38): 2:97,713,576-97,756,364 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q11.2 Autoimmune disease, multisystem, infantile-onset, 2 617006 Autosomal recessive 3
Immunodeficiency 48 269840 Autosomal recessive 3

TEXT

Description

The ZAP70 gene encodes a tyrosine kinase that is a critical T-cell signaling molecule that interacts with the zeta-chain (CD247; 186780) of the T-cell receptor (TCR). It is expressed predominantly in T and NK cells (summary by Chan et al., 2016).


Cloning and Expression

Chan et al. (1992) isolated a cDNA encoding a 70-kD tyrosine phosphoprotein, ZAP70, that associates with the zeta chain and undergoes tyrosine phosphorylation following TCR stimulation. The ZAP70 gene is expressed in T- and natural killer cells.


Mapping

Chan et al. (1994) mapped the ZAP70 gene to chromosome 2q12 by hybridization of a genomic fragment to human/rodent somatic hybrid cell DNA and by fluorescence in situ hybridization (FISH). Ku et al. (1994) likewise assigned the ZAP70 gene to 2q12 by isotopic in situ hybridization. They mapped the murine homolog to mouse chromosome 1 by the same method. Saito et al. (1997) also mapped the gene to mouse chromosome 1 and rat chromosome 9q22.1 by FISH; by genetic linkage analysis, they further refined the location of the gene on mouse chromosome 1.


Gene Function

Watts et al. (1996) identified a ZAP70 phosphorylation site on the erythrocyte band-3 protein (see 109270) cytoplasmic fragment. They found that this phosphorylation site is distinct from the phosphorylation sites for other PTKs.

Animals deficient in pre-TCR-alpha have few alpha-beta lineage cells but an increased number of gamma-delta T cells. These gamma-delta T cells exhibit more extensive TCR-beta rearrangement than gamma-delta T cells from wildtype mice. These observations are consistent with the idea that different signals emanating from the gamma-delta-TCR and pre-TCR instruct lineage commitment. Using confocal microscopy and biochemistry to analyze the initiation of signaling, Saint-Ruf et al. (2000) showed that the pre-TCR, but not the gamma-delta TCR, colocalizes with the p56(lck) Src kinase (153390) into glycolipid-enriched membrane domains (rafts) apparently without any need for ligation. This results in the phosphorylation of CD3-epsilon (186830) and ZAP70 signal transducing molecules. Saint-Ruf et al. (2000) stated that their results indicated clear differences between pre-TCR and gamma-delta-TCR signaling.

Colucci et al. (2002) noted that humans with mutations in ZAP70 have T-cell immunodeficiency, that mice lacking Zap70 have blocked T-cell development, and that mice lacking Syk (600085) have a failure of B-cell development. NK cells express both molecules, which associate with immunoreceptor tyrosine-based activation motifs (ITAMs). Using mice deficient in both Zap70 and Syk, Colucci et al. (2002) observed NK cell activity comparable to that in wildtype mice. The mutant cells expressed Nkg2d (602893) and were able to lyse targets with and without Nkg2d ligands in vitro and in vivo. However, wildtype cells, but not the double-deficient cells, responded to CD16 (146740) and Ly49d (see 604274) cross-linking with increased cytotoxicity, suggesting that these 2 ITAM-bearing receptors are unable to signal in the mutant cells. Inhibitors of PI3K (see 601232) or Src kinases blocked and, in combination, abrogated cytotoxic activity in the mutant cells, whereas inhibition of both kinases was required to reduce wildtype NK activity. Colucci et al. (2002) concluded that intracellular signaling in the adaptive immune system, i.e., in B and T cells, is fundamentally different from that in the NK cells of the innate immune system.

Sasahara et al. (2002) showed that the adaptor protein CRKL (602007) binds directly to WIP (602357) and that, following T-cell receptor ligation, a CRKL-WIP-WASP (300392) complex is recruited by ZAP70 to lipid rafts and immunologic synapses.

Crespo et al. (2003) found that ZAP70 expression by cells in chronic lymphocytic leukemia (CLL; 151400), as ascertained by flow cytometric analysis, is a simple and reliable surrogate for the identification of immunoglobulin heavy chain variable region gene (IGHV; see 147070) mutations. Moreover, ZAP70 expression by itself can be used as a prognostic marker. For these reasons, they urged that ZAP70 analysis be included in the workup of patients with CLL.

Using in vitro binding assays, Gu et al. (2006) showed that Rhoh (602037) interacted with Zap70. The Rhoh-Zap70 interaction depended mainly on conserved tyrosine-phosphorylated ITAMs in Rhoh and the SH2 domains in Zap70. Rhoh was required for proper recruitment of Zap70 to plasma membrane and cytoskeleton fractions in thymocytes and consequently for activation of Zap70 in TCR signal transduction. Based on these findings and studies in Rhoh -/- mice, Gu et al. (2006) concluded that RHOH is a critical regulator of thymocyte development and TCR signaling via its recruitment and activation of ZAP70.


Molecular Genetics

Immunodeficiency 48

In 3 affected females from 2 Mennonite families with immunodeficiency-48 (IMD48; 269840) characterized by a selective T-cell defect, Arpaia et al. (1994) identified a homozygous mutation in the ZAP70 (176947.0001), resulting in loss of the activity of this kinase. The mutation was present in heterozygous state in the parents and 3 unaffected sibs.

In 3 sibs, 2 boys and a girl, with IMD48, Chan et al. (1994) identified compound heterozygous mutations in the ZAP70 gene (176947.0002 and 176947.0003).

In a female infant with IMD48, Elder et al. (1994) identified a homozygous mutation in the ZAP70 gene (176947.0004). The parents and unaffected sibs were heterozygous for the mutation.

Chronic Lymphocytic Leukemia

Rassenti et al. (2004) noted that in cases of aggressive chronic lymphocytic leukemia (151400), CLL cells usually express an unmutated immunoglobulin heavy chain variable region gene (IGHV; see 147070) and ZAP70 gene, whereas in cases of indolent disease, CLL cells usually express a mutated immunoglobulin heavy chain variable region gene but lack expression of ZAP70. In studies of 307 patients with CLL, Rassenti et al. (2004) found that although the presence of an unmutated immunoglobulin heavy chain variable region gene was strongly associated with expression of ZAP70, ZAP70 was a stronger predictor of the need for treatment in B-cell CLL.

Infantile-Onset Multisystem Autoimmune Disease 2

In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006), Chan et al. (2016) identified compound heterozygous missense mutations in the ZAP70 gene (R192W, 176947.0006 and R360P, 176947.0007). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Studies of transfected cell lines and cells from the carrier parents showed that the R192W was a hypomorphic allele with reduced binding to phosphorylated zeta-chain (CD247; 186780) of the TCR, whereas R360P was weakly hyperactive compared to wildtype, most likely due to disruption of the autoinhibitory mechanism. The combination of hypomorphic and activating mutations suggested a novel disease mechanism resulting in a theretofore undescribed human ZAP70-associated autoimmune disease.


Animal Model

Sakaguchi et al. (2003) reported that the SKG strain, which is derived from a closed breeding colony of BALB/c mice, spontaneously develops chronic arthritis. Joint swelling with hyperemia became macroscopically evident in SKG mice at about 2 months of age, initially at a few interphalangeal joints of the forepaws, then progressing in a symmetrical fashion to swelling of the other finger joints of the forepaws and hindpaws and larger joints (wrists and ankles). Knee, elbow, shoulder, or vertebral joints were rarely affected except for the joint at the base of the tail in aged SKG mice. Radiographic examination revealed destruction and fusion of the subchondral bones, joint dislocation, and osteoporosis by 8 to 12 months of age. Despite suffering from such severe chronic arthritis, most SKG mice survived well to 1 year of age, generally with more severe arthritides in females. Sakaguchi et al. (2003) found that this arthritis is an autosomal recessive trait. They found a tryptophan-to-cysteine substitution at residue 163 (W163C) at the start of the second SH2 domain of ZAP70. Altered signal transduction from T-cell antigen receptor (see 186740) through the aberrant ZAP70 changes the threshold of T cells to thymic selection, leading to the positive selection of otherwise negatively selected autoimmune T cells. Sakaguchi et al. (2003) speculated that thymic production of arthritogenic T cells due to a genetically determined selection shift of the T-cell repertoire towards high self-reactivity might be crucial to the development of disease in a subset of patients with rheumatoid arthritis.


ALLELIC VARIANTS 7 Selected Examples):

.0001   IMMUNODEFICIENCY 48

ZAP70, IVS, G-A, -11
SNP: rs730880318, gnomAD: rs730880318, ClinVar: RCV000014158, RCV000726208, RCV001851845, RCV003390681

In 3 females in 2 different families from a genetically isolated Mennonite community in Ontario, Arpaia et al. (1994) demonstrated that immunodeficiency-48 (IMD48; 269840) due to a selective T-cell defect was the result of homozygosity for a splice mutation in the ZAP70 gene. An intronic point mutation created a new splice acceptor site with the insertion of 9 nucleotides in the mRNA and 3 additional amino acids in the protein product. The G-to-A transition at position -11 from the 3-prime end of the intron created an AluI restriction site which Arpaia et al. (1994) used for identifying heterozygotes in the family. Both parents were carriers and 3 of 4 sibs were heterozygous as well. The mutation resulted in an unstable protein that could not be detected by Western blotting or kinase activity.


.0002   IMMUNODEFICIENCY 48

ZAP70, IVS, G-A, -9
ClinVar: RCV000014158, RCV000726208, RCV001851845, RCV003390681

In 2 brothers and a sister with immunodeficiency-48 (IMD48; 269840), Chan et al. (1994) identified compound heterozygous mutations in the ZAP70 gene. One mutation, inherited from the mother, was a 9-bp insertion due to a G-to-A transition within an intron 9-bp upstream of the normal splice acceptor site. The mutation resulted in a more favored splice acceptor site (AGC rather than AGA) and in the addition of 3 amino acids, leu-glu-gln, within the catalytic domain of the ZAP70 protein. The other mutation, inherited from the father, was a 1763C-A transition resulting in a ser518-to-arg (S518R; 176947.0003) substitution. Ser518 is in a highly conserved region of the catalytic domain of the ZAP70 protein.


.0003   IMMUNODEFICIENCY 48

ZAP70, SER518ARG
SNP: rs104893674, ClinVar: RCV000033208

For discussion of the ser518-to-arg (S518R) mutation in the ZAP70 gene that was found in compound heterozygous state in patients with immunodeficiency-48 (IMD48; 269840) by Chan et al. (1994), see 176947.0002.


.0004   IMMUNODEFICIENCY 48

ZAP70, 13-BP DEL, NT1719
SNP: rs730880319, ClinVar: RCV000014164

In a 1-year-old female with immunodeficiency-48 (IMD48; 269840), Elder et al. (1994) demonstrated homozygosity for a 13-bp deletion involving nucleotides 1719-1731 (1719_1931del13) of the ZAP70 gene. The deletion would be expected to cause a translational frameshift after amino acid 503, resulting in premature termination 35 codons downstream and yielding a mutant protein 82 residues shorter than the wildtype. Both parents and 2 unaffected sibs were heterozygous for the mutation.


.0005   IMMUNODEFICIENCY 48

ZAP70, ARG465HIS
SNP: rs137853201, gnomAD: rs137853201, ClinVar: RCV000033214, RCV001305022

In an 8-month-old girl with immunodeficiency-48 (IMD48; 269840), Toyabe et al. (2001) detected a homozygous 1603G-A transition in the ZAP70 gene, resulting in an arg465-to-his substitution in the kinase domain. The patient lacked CD8-positive T cells but had normal CD4-positive T cells and serum Ig levels. ZAP70-deficient patients rarely have antigen-specific antibodies, but this patient developed specific IgE antibodies (see 147050) to food allergens without developing food allergies. Stimulation of peripheral blood mononuclear cells with phorbol myristate acetate, but not with other mitogens, resulted in production of high levels of IL4 (147780), T-cell expression of CD40L (300386), and expression of germline and mature IgE epsilon transcripts in B cells. Western blot analysis showed expression of high levels of SYK (600085) in T cells from the patient, which also expressed high levels of CD40L, but not in those from controls. A protein tyrosine kinase/SYK inhibitor aborted IL4 production and CD40L expression. Toyabe et al. (2001) proposed that partial T-cell function and a T-cell receptor-signaling pathway can be retained in some ZAP70-deficient patients via SYK.


.0006   AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)

ZAP70, ARG192TRP
SNP: rs199840952, gnomAD: rs199840952, ClinVar: RCV000208562, RCV000227350, RCV001559120, RCV001853323

In 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006), Chan et al. (2016) identified compound heterozygous mutations in the ZAP70 gene: a c.574C-T transition (c.574C-T, NM_001079.3) in exon 5, resulting in an arg192-to-trp (R192W) substitution in the phosphotyrosine-binding pocket, and a c.1079G-C transversion in exon 9, resulting in an arg360-to-pro (R360P; 176947.0007) substitution in the N-lobe of the kinase domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Transfection of the mutations into HEK293 T cells showed that the R192W mutant had reduced association with phosphorylated zeta-chains, consistent with it being a hypomorphic allele. Transfection of the R360P mutant did not result in constitutive LAT phosphorylation, but nearby D327P and K362E mutants did cause increased activity, suggesting that all these mutations may interfere with proper autoinhibition of ZAP70. Further studies in another T-cell line indicated that the R360P mutant is weakly hyperactive due to disruption of its autoinhibitory mechanism. Patient cells were not available because both patients had undergone hematopoietic stem cell transplantation, but studies of cells from the heterozygous parents were consistent with R192W being a hypoactive mutant and R360P being weakly hyperactive. Finally, double-transfected cells showed that the R360P phenotype was masked by wildtype ZAP70 and revealed only in the presence of the hypoactive R192W allele.


.0007   AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 2 (1 family)

ZAP70, ARG360PRO
SNP: rs869025224, ClinVar: RCV000208547, RCV000233631, RCV001559121

For discussion of the c.1079G-C transversion (c.1079G-C, NM_001079.3) in exon 9 of the ZAP70 gene, resulting in an arg360-to-pro (R360P) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset multisystem autoimmune disease-2 (ADMIO2; 617006) by Chan et al. (2016), see 176947.0006.


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Contributors:
Bao Lige - updated : 03/14/2019
Cassandra L. Kniffin - updated : 6/27/2016
Victor A. McKusick - updated : 9/13/2004
Ada Hamosh - updated : 12/1/2003
Victor A. McKusick - updated : 6/6/2003
Stylianos E. Antonarakis - updated : 4/28/2003
Paul J. Converse - updated : 2/11/2002
Paul J. Converse - updated : 7/17/2001
Ada Hamosh - updated : 8/2/2000
Jennifer P. Macke - updated : 5/27/1998
Victor A. McKusick - updated : 2/12/1997

Creation Date:
Victor A. McKusick : 12/3/1992

Edit History:
carol : 05/27/2020
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mgross : 03/14/2019
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carol : 07/07/2016
alopez : 6/28/2016
ckniffin : 6/27/2016
carol : 2/10/2015
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mgross : 2/11/2014
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joanna : 12/14/2012
carol : 10/25/2012
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carol : 4/8/2002
alopez : 3/12/2002
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mgross : 7/17/2001
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carol : 8/18/1998
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dholmes : 5/27/1998
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dholmes : 4/16/1998
terry : 2/12/1997
terry : 2/7/1997
mimadm : 2/25/1995
carol : 1/27/1995
jason : 6/21/1994
carol : 12/3/1992