Immunodeficiency 48

A number sign (#) is used with this entry because immunodeficiency-48 (IMD48), characterized by selective T-cell defect (STCD), is caused by homozygous or compound heterozygous mutation in the ZAP70 gene (176947) on chromosome 2q11.

Clinical Features

Roifman et al. (1989) described a female infant with a novel type of human immunodeficiency characterized by a selective T-cell defect. Peripheral circulating T cells from these patients exclusively expressed CD4, CD3, and T-cell receptor-alpha/beta, but not CD8 molecules on their surface. The inability to produce peripheral CD8 single-positive cells was traced to an intrathymic developmental defect. Whereas CD4(+)/CD8(+)-positive cells were present in the thymic cortex of these patients, only CD4, not CD8, single-positive cells could be detected in the thymic medulla, suggesting a selective block of positive selection of CD8+ cells. Peripheral CD4+ T cells from this patient failed to proliferate in response to mitogens or to treatment with anti-CD3 antibody. The patient's older sib had been diagnosed with severe combined immunodeficiency.

Monafo et al. (1992) reported 2 brothers and 2 sisters of separate Mennonite families, with reportedly unrelated parents, with severe immunodeficiency associated with absence of CD8+ T lymphocytes and normal numbers of CD4+ T lymphocytes that did not respond to stimulation by nonspecific mitogens, specific antibodies against the T-cell receptor, or specific antigens. One of the sisters had previously been reported in detail by Roifman et al. (1989). Monafo et al. (1992) found that the defect in the CD4+ cells was bypassed by activating agents that are independent of the T-cell receptor. The combination of an activation defect and selective depletion of CD8+ T lymphocytes suggested that the defective pathway was important in the differentiation of mature lymphocytes. Clinical findings included tonsils that were moderate in size and lymph nodes that were easily palpated. Serum immunoglobulin concentrations were increased or normal. All 4 children received bone marrow transplants.

Elder et al. (1994) reported studies of a 1-year-old girl, the daughter of first cousins, in whom immunodeficiency was associated with a highly unusual T-cell subset distribution in the blood. The overall T-cell count was moderately elevated, but CD8+ cells were virtually absent and nearly all circulating T cells were of the CD4+ type. The patient was subsequently cured of her disease by bone marrow transplantation.

Toyabe et al. (2001) reported an 8-month-old immunodeficient girl with ZAP70 deficiency who lacked CD8-positive T cells but had normal CD4-positive T cells and serum Ig levels. Toyabe et al. (2001) noted that 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.

Molecular Genetics

Because the phenotype of STCD T cells was consistent with a deficiency of a T cell-specific protein-tyrosine kinase, Arpaia et al. (1994) screened the cells of 3 patients with STCD from 2 Mennonite families for a possible mutation in these genes. They identified a homozygous mutation in the ZAP70 gene (176947.0001) which resulted in loss of the activity of this kinase. The parents and 3 unaffected sibs were heterozygous for the mutation.

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

In a 1-year-old girl with selective T-cell defect, Elder et al. (1994) identified a homozygous mutation in the ZAP70 gene (176947.0004). Both parents and 2 unaffected sibs were heterozygous for the mutation.

In an 8-month-old girl with selective T-cell defect, Toyabe et al. (2001) detected a homozygous mutation in the ZAP70 gene (176947.0005).