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ZAP70-Related Severe Combined Immunodeficiency

Synonym: Zeta-Associated Protein 70 Deficiency

, MD and , MD.

Author Information
, MD
Division of Allergy and Immunology
Children’s Hospital of Pittsburgh
Pittsburgh, Pennsylvania
, MD
Division of Allergy and Immunology
Children’s Hospital of Pittsburgh
Pittsburgh, Pennsylvania

Initial Posting: ; Last Revision: September 6, 2012.

Summary

Disease characteristics. ZAP70-related severe combined immunodeficiency (ZAP70-related SCID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling. Affected children usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower respiratory infections and oral moniliasis are common. Affected children usually do not survive past their second year without hematopoietic stem cell transplantation (HSCT).

Diagnosis/testing. The diagnosis is established by lymphocyte counts (particularly of CD3, CD4, and CD8 T cells), lymphocyte function testing, ZAP-70 protein expression, and ZAP70 molecular genetic testing.

Management. Treatment of manifestations: Short-term treatment includes immediate intravenous immunoglobulin (IVIG) and antibacterial, antifungal, and anti-protozoal prophylaxis to control and reduce the occurrence of infections.

Prevention of primary manifestations: Allogeneic HSCT to reconstitute the immune system, preferably within the first three months of life.

Prevention of secondary complications: Use of irradiated, cytomegalic virus (CMV), Epstein Barr Virus (EBV)-negative blood products; deferment of immunizations until immune reconstitution.

Surveillance: Following a successful HSCT, monitoring of the following every two to six months: immune status, liver and renal function, complete blood count, growth, and psychomotor development.

Agents/circumstances to avoid: Non-irradiated blood products; live viral and live bacterial vaccinations.

Evaluation of relatives at risk: Because the outcome in children with SCID is significantly improved by HSCT in the first three months of life, consider early testing to establish the genetic status of at-risk sibs.

Genetic counseling. ZAP70-related SCID is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic allelic variants in the family are known.

Diagnosis

Clinical Diagnosis

ZAP70-related severe combined immunodeficiency (ZAP70-related SCID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling leading to a selective absence of CD8+ T cells and normal or elevated numbers of non-functional CD4+ T cells [Arpaia et al 1994, Chan et al 1994, Elder et al 1994].

Children usually present in the first year of life with failure to thrive and recurrent viral, bacterial, and opportunistic infections.

Testing

The diagnosis of ZAP70-related SCID relies on lymphocyte subset analysis of CD3, CD4, and CD8 T cells, lymphocyte function testing, ZAP-70 protein expression, and ZAP70 molecular genetic testing.

Lymphocyte counts and lymphocyte cell surface expression. In ZAP70-related SCID, total lymphocyte counts can range from normal to high.

  • T cell counts
  • B cell counts and NK cell counts. Normal

Lymphocyte function. T-cell responses to stimuli that act through the T-cell receptor (TCR) are absent or severely diminished:

Note: T-cell responses to phorbol myristic acetate and ionomycin stimulation (which bypasses the TCR) are normal [Elder et al 1994, Elder 1997].

ZAP-70 protein expression. Immunocytochemistry testing of CD4+ T cells reveals absence of ZAP-70 protein in most cases. Note: (1) Two reports have described defects leading to protein expression with either rapid protein degradation [Matsuda et al 1999] or no catalytic function [Elder et al 2001]. (2) One report describes a hypomorphic ZAP70 mutation leading to decreased protein expression and function with late-onset combined immunodeficiency [Picard et al 2009].

Immunoglobulin concentrations and function

  • Immunoglobulin levels vary by individual. A majority of affected individuals have severe hypogammaglobulinemia, but hypergammaglobulinemia and normal immunoglobulin levels have been seen [Turul et al 2009].
  • Although functional antibody responses to immunization are present in a few persons [Turul et al 2009], this finding does not indicate that all specific antigenic responses are intact.

Molecular Genetic Testing

Gene. ZAP70 is the only gene in which mutations cause ZAP70-related severe combined immunodeficiency.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in ZAP70-Related Severe Combined Immunodeficiency

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ZAP70Sequence analysis 4Sequence variants15/15 5

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. At least 15 individuals meeting diagnostic criteria have had identifiable ZAP70 mutations [Arpaia et al 1994, Chan et al 1994, Elder et al 1994, Matsuda et al 1999, Noraz et al 2000, Elder et al 2001, Meinl et al 2001, Toyabe et al 2001, Picard et al 2009, Turul et al 2009].

Testing Strategy

To confirm/establish the diagnosis in a proband, the following evaluations should be considered:

  • Lymphocyte cell surface expression of CD3, CD4, and CD8
  • Lymphocyte functional response to mitogens, antigens, and biochemical agents like phorbol myrsitate acetate and ionomycine
  • Immunohistochemistry for presence of ZAP-70 protein
  • Immunoglobulin level and specific antibody responses
  • Molecular genetic testing for mutations in ZAP70 may be helpful to confirm a diagnosis due to the clinical heterogeneity of ZAP70-related SCID [Turul et al 2009] (see Testing).

Newborn screening. The use of routine newborn screening for T SCID by measuring T-cell receptor excision circle (TREC) levels continues to increase. Despite normal quantitative levels of CD4 cells in individuals with ZAP70-related SCID, TREC levels in already known cases of ZAP70-related SCID were found to be very low compared to age-matched controls [Roifman et al 2010], suggesting that detection of ZAP70-related SCID may be possible through newborn screening methods utilizing TREC quantitation.

Carrier testing for at-risk relatives requires prior identification of the pathogenic allelic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Description

Natural History

Individuals with ZAP70-related SCID usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower respiratory infections are typically seen, most notably Pneumocystis jiroveci infections and viral infections. Oral moniliasis is common.

Whereas the above presentation is characteristic of ZAP70-related SCID, there are exceptions:

Other presenting findings [Elder et al 1995, Parry et al 1996, Turul et al 2009]:

  • Subcutaneous nodules
  • Lymphadenopathy
  • Exfoliative dermatitis
  • Thrombocytopenia
  • Chronic gastroenteritis
  • Ulcerative colitis

The long-term prognosis of untreated ZAP70-related SCID is death from infection. Affected children have a declining quality of life and usually do not survive past their second year without HSCT. A long-term study found that following HSCT, three-year survival rates were 77% and 54% for HLA-identical and HLA-mismatched transplants respectively [Antoine et al 2003, Müller & Friedrich 2005]. Note: Survival rates given are for cohorts that comprise various forms of SCID, including ZAP70-related SCID; statistical outcomes specifically for ZAP70-related SCID are unknown.

Children with preexisting viral infections are at increased risk of developing graft-versus-host disease (GVHD) following HSCT, leading to a poor prognosis [Dvorak & Cowan 2008].

Genotype-Phenotype Correlations

A possible genotype-phenotype correlation is illustrated in a child with a hypomorphic intronic mutation (c.837+121G>A in intron 7) who had had chronic eczema from age two months and recurrent infections from age two years. Other findings in this child:

  • Low levels of alternative splicing resulting in 20% expression of ZAP-70 protein in T cells and partial T-cell activation
  • Low overall T-lymphocyte count
  • Low CD8+ cell count typical of ZAP70-related SCID
  • Low CD4+ cell counts (atypical for ZAP70-related SCID)

Each infection was treated individually until age six years, when the frequency of infection declined following introduction of cotrimoxazole and IVIG prophylaxis. Of note, an older sib with a history of multiple infections had died at age one year [Picard et al 2009].

Prevalence

The prevalence of ZAP70-related SCID is unknown but much lower than that of all forms of SCID, which is estimated at 1:50,000.

ZAP70-related SCID was first described in 1994. About 20 cases have been described in the literature [Fischer et al 2010].

Most cases of ZAP70-related SCID have occurred in genetically isolated Mennonite communities and/or in offspring of consanguineous relationships.

Differential Diagnosis

Infants positive for human immunodeficiency virus (HIV+) may present with recurring infections and failure to thrive similar to SCID. Individuals with HIV have CD4+ lymphopenia, in contrast to the CD8+ lymphopenia in ZAP70-related SCID. In a neonate the definitive diagnosis of HIV should be made by detection of cell-associated human immunodeficiency proviral DNA by polymerase chain reaction (PCR) amplification. See Table 2.

Table 2. Combined Immunodeficiencies in the Differential Diagnosis of ZAP70-Related SCID

Disease NameGene InvolvedMode of InheritanceLymphocyte Phenotype
TBNKOther
Familial CD8 deficiencyCD8AAR+++CD4+/CD8
CD25 deficiency IL2RAAR+++CD4/CD8+
MHC II deficiency (BLS)See Major histocompatibility complex (below) AR+++CD4/CD8+

MHC II = major histocompatibility complex class II

BLS = bare lymphocyte syndrome

Familial CD8 deficiency (OMIM 608957) may have a presentation similar to ZAP70-related SCID, but the diagnosis can be confirmed with CD8A molecular genetic testing. The two individuals reported with this disease had recurring infections from early childhood and lived past their twenties [de la Calle-Martin et al 2001, Mancebo et al 2008].

CD25 deficiency (OMIM 606367) also presents with recurring infections early in life with low to normal T-cell counts. However, the T cells are CD4/CD8+. The diagnosis can be confirmed with molecular genetic testing of IL2RA (CD25), which encodes the interleukin-2 receptor alpha chain.

Major histocompatibility complex (MHC) class II deficiency (also known as bare lymphocyte syndrome) (OMIM 209920) may have normal or elevated T-cell counts; however, the T cells are CD4/CD8+. As in other forms of SCID, pathologic findings manifest within the first year of life. Major histocompatibility complex II expression is decreased. Molecular genetic testing may reveal mutations in RFX5, RFXAP, MHC2TA, or RFXANK, the four genes in which mutation is known to cause this disorder.

Table 3 differentiates several forms of severe combined immunodeficiency. Since SCID presents as a phenotypically heterogeneous class of diseases, it is useful to recognize forms of SCID that present with low to normal T-cell counts. Lymphocyte subset testing and molecular genetic testing can implicate or eliminate these other forms of SCID.

Table 3. T-Cell-Negative Forms of SCID in the Differential Diagnosis of ZAP70-Related SCID

Disease NameGene InvolvedDefectMode of InheritanceLymphocyte Phenotype
TBNK
ZAP70-related SCIDZAP70Decreased protein expressionAR+++
JAK3-related SCIDJAK3AR+
IL7RA-related SCIDIL7RAAR++
CD45 deficiencyCD45AR+
ADA deficiencyADADecreased protein productionAR
RAG1/2 deficiency RAG1, RAG2AR+
SCID AthabascanARTEMISAR+
X-linked SCIDIL2RGDysfunctional receptorXLR+

Omenn syndrome (OMIM 603554). Two children with ZAP70-related SCID presented with an Omenn syndrome-like phenotype that included lymphadenopathy, hepatosplenomegaly, and eosinophilia. Lymphocyte subset tests consistent with ZAP70-related SCID in both cases eliminated Omenn syndrome as a possible diagnosis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ZAP70-related severe combined immunodeficiency (SCID), the following evaluations are recommended:

  • Evaluation for common and opportunistic viral, bacterial, and fungal disease-causing agents
  • Assessment of growth
  • Complete metabolic panel (liver and renal function) and CBC with differential and platelet count
  • Medical genetics consultation
  • Immunology consultation, if not performed already

Treatment of Manifestations

Treatment relies on prompt reconstitution of the individual’s immune system (see Prevention of Primary Manifestations).

Short-term treatment includes immediate intravenous immunoglobulin (IVIG) and antibacterial, antifungal, and anti-protozoal prophylaxis to control and reduce the occurrence of infections.

Prevention of Primary Manifestations

The standard of therapy to cure SCID is allogeneic hematopoietic stem cell transplantation (HSCT). The outcome of HSCT in children with SCID is significantly improved by performing HSCT in the first three months of life [Buckley 2004]. Several children with ZAP70-related SCID have been transplanted [Arpaia et al 1994, Elder et al 1994, Elder et al 2001, Noraz et al 2000].

  • Outcomes are the best with HLA-matched, related donors.
  • If a related, HLA-matched donor is not available, alternatives include:
    • Matched unrelated donor
    • Umbilical cord blood donor
    • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T cell depleted
  • In contrast to individuals with other forms of SCID, individuals with ZAP70-related SCID are typically treated with a chemotherapeutic conditioning regimen prior to HSCT.
    • Hönig et al [2012] described the successful use of lymphocyte transfusion from a previously transplanted HLA identical sib without the use of conditioning for reconstituting the immune system in an individual with ZAP70-SCID.
  • Cellular reconstitution following HSCT takes three to four months and restoration of humoral immunity can take one to two years or more.
  • Complications from HSCT include graft-versus-host disease, failure to reconstitute the humoral immune compartment, graft failure over time, and post-transplant lymphoproliferative disease [Skoda-Smith et al 2001].
  • Affected individuals with poor humoral reconstitution are maintained on long-term immunoglobulin replacement.

Individuals with mild initial findings are maintained on immunoglobulin replacement and prophylactic antimicrobial therapy. They need to be monitored for worsening of immune function manifest by increased susceptibility to severe or opportunistic infections (see also Surveillance). If clinical status worsens, curative HSCT should be considered.

Prevention of Secondary Complications

The following are appropriate:

  • Use of irradiated, CMV-negative blood products

    Note: While not routinely screened for, the use of blood products from a known Epstein-Barr virus (EBV)-negative source should be considered as EBV-related lymphoma has been described in ZAP70-SCID [Newell et al 2011].
  • Delay of immunizations until immune reconstitution

Surveillance

Following a successful HSCT, the following should be monitored every six to 12 months:

  • Immune status
  • Liver and renal function
  • Complete blood count
  • Growth
  • Psychomotor development

Individuals with milder findings need to be monitored for worsening of immune function with at least semiannual assessment of clinical status and functional lymphocyte responsiveness.

Agents/Circumstances to Avoid

Individuals with ZAP70-related SCID should never receive the following:

  • Non-irradiated blood products
  • Live virus vaccinations
  • Mycobacterium bovis (BCG) vaccine against tuberculosis, Salmonella typhi (Ty21a) vaccine against typhoid fever, and Vibrio cholerae (CVD 103-HgR) vaccine against cholera, which may be part of the routine vaccination schedule in countries where these diseases are endemic

Evaluation of Relatives at Risk

Because the outcome of HSCT in children with SCID is significantly improved by performing HSCT in the first three months of life, early testing of at-risk sibs should be considered.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

An affected pregnant mother should receive prenatal counseling. Appropriately screened blood products should be available, if needed, during the course of the pregnancy or delivery.

Therapies Under Investigation

Gene therapy. While gene therapy has been used for other forms of SCID (notably ADA deficiency and X-linked SCID), it has not been performed in ZAP70-related SCID. Experimental studies utilizing gene therapy for this disease have been conducted on murine models [Adjali et al 2005, Irla et al 2008] as well as human cells in vitro [Steinberg et al 2000, Kofler et al 2004].

Adverse oncogenic reactions have been documented in some individuals with X-linked SCID transduced with retroviral vector [Buckley 2003, Fischer et al 2005]. The role of nonviral transfer methods (e.g., electro-gene transfer) have been used to correct ZAP-70 deficiency in a murine model [Irla et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ZAP70-related severe combined immunodeficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Each parent is a carrier for a pathogenic variant in ZAP70.
  • While parents do not usually have SCID-like symptoms, Turul et al [2009] analyzed the ZAP70 expression in the parents of probands and demonstrated that parents have intermediate expression levels compared to healthy controls. The implications of this finding have not been determined [Turul et al 2009].

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their gene status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants.

Offspring of a proband

  • The offspring of an individual with ZAP70-related severe combined immunodeficiency will inherit one pathogenic variant from the proband.
  • The genetic status of the offspring will depend on the genetic status of the reproductive partner of the proband.
    • If the reproductive partner is not affected and not a carrier, all offspring will be carriers.
    • If the reproductive partner is a carrier of a pathogenic variant in ZAP70, each child will have a 50% chance of being affected and a 50% chance of being a carrier.
    • If the reproductive partner is also affected, all offspring will be affected.
  • Most individuals with ZAP70-related SCID are from genetically isolated Mennonite communities and/or have consanguineous parents.

Other family members. A detailed family history that includes the ancestry and culture of the proband’s family may reveal consanguinity and geographic and genetic isolation – risk factors that increase the likelihood of autosomal recessive diseases in a family. Some of the grandparents of the proband are carriers for ZAP70 pathogenic variants; therefore, sibs of the proband’s parents and their offspring are at risk of being carriers.

Carrier Detection

Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variants have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

An affected fetus does not require any specific management prior to delivery. Following delivery, early evaluation for potential HSCT should be performed because of the known benefit of early HSCT.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Immune Deficiency Foundation (IDF)
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204
    Phone: 800-296-4433 (toll-free)
    Email: idf@primaryimmune.org
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Firside
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
    Email: info@ipopi.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • Canadian Immunodeficiencies Patient Organization (CIPO)
    362 Concession Road 12
    RR #2
    Hastings Ontario K0L 1Y0
    Canada
    Phone: 877-262-2476 (toll-free)
    Fax: 866-942-7651 (toll-free)
    Email: info@cipo.ca
  • National Human Genome Research Institute (NHGRI)
  • NCBI Genes and Disease
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org
  • Primary Immunodeficiency Diseases Registry at USIDNET
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204-4803
    Phone: 866-939-7568
    Fax: 410-321-0293
    Email: contact@usidnet.org
  • RDCRN Patient Contact Registry: Primary Immune Deficiency Treatment Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. ZAP70-Related Severe Combined Immunodeficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for ZAP70-Related Severe Combined Immunodeficiency (View All in OMIM)

176947ZETA-CHAIN-ASSOCIATED PROTEIN KINASE; ZAP70
269840SELECTIVE T-CELL DEFECT; STCD

Gene structure. ZAP70 spans 26.3 kb of genomic DNA. The gene consists of 14 exons comprising 2450 bp. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. ZAP70 pathogenic variants reside mostly in the kinase domain, although mutations that result in loss of transcription or are located in the N-terminal SH2 domain and result in rapid degradation of ZAP-70 protein have been reported [Matsuda et al 1999, Au-Yeung et al 2009]. More than a dozen mutations consisting of single point mutations, splice defects, and intragenic deletions have been reported. A pathogenic variant in the arginine residue (p.Arg465Cys) of the DLAARN motif of the kinase domain has been described (see Abnormal gene product). Selected pathogenic variants can be viewed in Table 4 and Table A. Details on other pathogenic variants may also be found in the review article Wang et al [2010] and in Fischer et al [2010].

Table 4. Selected ZAP70 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.239C>A
(448C>A)
p.Pro80GlnNM_001079​.3
NP_001070​.2
c.837+121G>A
(836+121G>A)
See Abnormal gene product
c.1393C>Tp.Arg465Cys
c.1714A>T
(1923A>T)
p.Met572Leu

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. ZAP70 codes for an enzyme in the Syk-protein tyrosine kinase family that plays a role in T-cell development and activation. This enzyme is phosphorylated at tyrosine residues upon T-cell receptor (TCR) stimulation and functions in the initial step of TCR-mediated signal transduction with Src family kinases. ZAP-70 comprises 619 amino acids and contains two SH2 domains and one kinase domain. The mutations that lead to ZAP70-related SCID occur in or close to the region coding the kinase domain.

Abnormal gene product. Most noted mutations affect the kinase domain of ZAP70 and cause a lack of protein expression. The p.Arg465Cys alteration in the highly conserved DLAARN motif of the kinase domain compromises ZAP-70 protein stability and eliminates the protein’s catalytic function [Elder et al 2001]. Both the p.Pro80Gln and p.Met572Leu altered proteins undergo temperature-sensitive degradation [Matsuda et al 1999]. Picard et al [2009] described a hypomorphic mutation in ZAP70 intron 7 (c.837+121G>A) that creates a new in-frame splice product with a new stop codon within intron 7. In addition to the truncated product, the mutation allowed residual expression of the wild type protein (20% expression level in the patient’s T cells) and an attenuated clinical and immunologic phenotype (see Genotype-Phenotype Correlations) [Picard et al 2009].

References

Literature Cited

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  2. Antoine C, Müller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A. European Group for Blood and Marrow Transplantation; Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003;361:553–60. [PubMed: 12598139]
  3. Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking ZAP-70 kinase. Cell. 1994;76:947–58. [PubMed: 8124727]
  4. Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, Weiss A. The structure, regulation, and function of ZAP-70. Immunol Rev. 2009;228:41–57. [PubMed: 19290920]
  5. Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625–55. [PubMed: 15032591]
  6. Buckley RH. Treatment options for genetically determined immunodeficiency. Lancet. 2003;361:541–2. [PubMed: 12598135]
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  8. de la Calle-Martin O, Hernandez M, Ordi J, Casamitjana N, Arostegui JI, Caragol I, Ferrando M, Labrador M, Rodriguez-Sanchez JL, Espanol T. Familial CD8 deficiency due to a mutation in the CD8 alpha gene. J Clin Invest. 2001;108:117–23. [PMC free article: PMC209336] [PubMed: 11435463]
  9. Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008;41:119–26. [PubMed: 17968328]
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  11. Elder ME. SCID due to ZAP-70 deficiency. J Pediatr Hematol Oncol. 1997;19:546–50. [PubMed: 9407944]
  12. Elder ME, Hope TJ, Parslow TG, Umetsu DT, Wara DW, Cowan MJ. Severe combined immunodeficiency with absence of peripheral blood CD8+ T cells due to ZAP-70 deficiency. Cell Immunol. 1995;165:110–7. [PubMed: 7671314]
  13. Elder ME, Skoda-Smith S, Kadlecek TA, Wang F, Wu J, Weiss A. Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70. J Immunol. 2001;166:656–61. [PubMed: 11123350]
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Suggested Reading

  1. Pessach IM, Notarangelo LD. Gene therapy for primary immunodeficiencies: looking ahead, toward gene correction. J Allergy Clin Immunol. 2011;127:1344–50. [PMC free article: PMC3105180] [PubMed: 21440291]

Chapter Notes

Author History

Tara Capece, MPH; University of Pittsburgh (2009-2012)
Marc Ikeda, MD (2012-present)
Allyson Larkin, MD (2012-present)
David Nash, MD; Children’s Hospital of Pittsburgh (2009-2012)

Revision History

  • 6 September 2012 (cd) Revision: prenatal diagnosis available clinically
  • 1 March 2012 (me) Comprehensive update posted live
  • 20 October 2009 (me) Review posted live
  • 1 June 2009 (tc) Original submission
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