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ZAP-70 deficiency

Chaim M Roifman, MD, FRCPC, FCACB
Section Editor
Jennifer M Puck, MD
Deputy Editor
Elizabeth TePas, MD, MS


The zeta chain-associated protein kinase of 70 kD (ZAP-70) is involved in T cell receptor (TCR) signaling and is critical for T cell differentiation and function. Deficiency of ZAP-70 causes a combined immunodeficiency (CID). Affected children present within the first two years of life with a history of recurrent infections, similar to infants with severe combined immunodeficiency (SCID). However, diagnosis can be delayed because most patients with ZAP-70 deficiency have detectable lymphoid tissues and a normal lymphocyte count. The treatment of choice is hematopoietic cell transplantation (HCT).

A review of ZAP-70 deficiency (MIM +176947) is discussed here. Reviews related to other CIDs are presented separately. SCID disorders are also discussed separately. (See "CD3/T cell receptor complex disorders causing immunodeficiency" and "Combined immunodeficiencies" and "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)

TCR genetics, structure, biology, and signaling are covered in detail separately as well. (See "T cell receptor genetics" and "The adaptive cellular immune response", section on 'T cell activation' and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Overview of T cell receptor biology' and "T cell receptor signaling".)


T cell receptor (TCR) signaling in naïve T cells is initiated by binding of TCR to a peptide-major histocompatibility (MHC) complex expressed on the surface of antigen-presenting cells (figure 1 and figure 2). This association leads to activation of multiple pathways eventually culminating in a T cell response. The Src-family protein tyrosine kinase Lck is first activated with resultant phosphorylation of motifs known as immune receptor tyrosine-based activation motifs (ITAMs). Phosphorylated ITAMs on CD3 zeta serve as binding sites for ZAP-70. ZAP-70 is also activated by autophosphorylation. The role of this kinase in TCR signaling was unveiled by studying humans with ZAP-70 deficiency. Activated ZAP-70 phosphorylates a variety of downstream molecules, resulting in calcium mobilization, actin cytoskeleton rearrangement, and activation of Ras guanosine triphosphate hydrolase (GTPase). These events lead to activation of several transcription factors with resultant T cell proliferation and differentiation. (See "T cell receptor signaling".)


ZAP-70 deficiency is a rare combined immunodeficiency (CID) with an autosomal recessive pattern of inheritance. The disease was first described in 1989 in a patient of Mennonite descent with CD8 lymphocytopenia [1]. Mutations in ZAP-70 were initially identified in Mennonite kindreds and subsequently in Hispanics, Japanese, Turkish, and Portuguese patients [2-8].

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Literature review current through: Sep 2017. | This topic last updated: Apr 06, 2016.
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