Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature

Shirkani, Afshin; Shahrooei, Mohammad; Azizi, Gholamreza; Rokni‐Zadeh, Hassan; Abolhassani, Hassan; Farrokhi, Shokrollah; Frans, Glynis; Bossuyt, Xavier; Aghamohammadi, Asghar

doi:10.1080/08820139.2016.1214962

Cited by 17 publications

(6 citation statements)

References 36 publications

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“…In contrast to the Iranian boy with the same missense mutation who suffered form autoimmune hemolytic anemia and immune thrombocytopenia anemia (in supplemental Table 3), 52 our patient distinctly developed autoimmune hepatitis and transient gross hematuria (reversible gromerulonephritis) as well as hypogammaglobulinemia. These two boys also experienced IBD-like diarrhea.…”

Section: Discussioncontrasting

confidence: 83%

Lymphocyte Disturbance in The [Asp521Asn] ZAP70 Mutation and An Overview of All Phenotype/Genotype

Lee

Lin

et al. 2021

Preprint

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Background. Activated Zeta (ζ)-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαβ:CD3:ζ-complex to diversify the initial TCR signal. Patients with the ZAP70 mutations could present with the phenotype of immune dysregulation. Methods. We identified the first Taiwanese boy with the ZAP70 mutation, assessed downstream signaling, investigated lymphocyte disturbance and analyzed all available phenotype/genotype for optimal treatment.Results. With the [Asp521Asn]ZAP70 mutation, the infant who had hypogammaglobulinemia, eosinophilia, isolated CD8 lymphopenia, and impaired lymphocyte proliferation experienced recurrent pneumonia, refractory diarrhea, transient hematuria and autoimmune hepatitis. Decreased CD3/CD28 downstream phosphorylation of AKT, ZAP70 and Ca2+ influx related to the Th2-skewing T follicular helper cells, expanded transitional B, increased CD21-low B cells and lower Treg cells. To speculate clinical course for effective treatment, we overviewed 45 available published patients. Except for two asymptomatic post-transplant infants, common pathogens were oral candida (n=9), PJP (n=7), CMV (n=5), varicella (n=4), parainfluenza (n=3) and disseminated BCG (n=3). Their phenotypes of immune dysregulation mainly included IBD-like diarrhea (n=12), dermatitis (n=7), hepatosplenomegaly (n=3) and nephritic syndrome (n=3). Founder-effect or hot-spot mutations (32/90 alleles) involving the kinase domain clustered on intron 12 [1624-11G>A] (in 24) and exon 12[1520C>T] (in 8). Eleven died of sepsis (n=3), CMV pneumonitis (n=2), viral encephalitis, disseminated measles-vaccine infection, ARDS, HLH-like, EBV-lymphoproliferative disorder, and lymphoma each. Whatever developing opportunistic infections (p=0.2240), immune dysregulation (p=0.5268), or failure to thrive (p=0.5215), those who receiving HSCT had significantly better prognosis (p=0.0003). Conclusions. The Asp521Asn-ZAP70 hinders TCR-CD3 downstream phosphorylation and disturbs lymphocyte subgroup “profiles” leading to autoimmune/autoinlfmmation. The lymphocyte disturbance should be validated in large-scale studies. Receiving HSCT is a significantly better survival factor, rather than mutation types, opportunistic infections, or immune dysregulation.

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Section: Discussioncontrasting

confidence: 83%

Lymphocyte Disturbance in The [Asp521Asn] ZAP70 Mutation and An Overview of All Phenotype/Genotype

Lee

Lin

et al. 2021

Preprint

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“…This enzyme, phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn and plays an essential role in the process of thymocyte development [66]. In addition, mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells [67]. Leite et al investigated the expression of ZAP70 in cows naturally infected with MAP and revealed that the surface expression of ZAP70 was decreased in CD4+ T cells of both subclinical and clinical animals indicating a change in T cell phenotype with disease state [68].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of Mycobacterium avium subspecies Paratuberculosis infection in Chinese Holstein

et al. 2018

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BackgroundParatuberculosis is a contagious, chronic and enteric disease in ruminants, which is caused by Mycobacterium avium subspecies paratuberculosis (MAP) infection, resulting in enormous economic losses worldwide. There is currently no effective cure for MAP infection or a vaccine, it is thus important to explore the genetic variants that contribute to host susceptibility to infection by MAP, which may provide a better understanding of the mechanisms of paratuberculosis and benefit animal genetic improvement. Herein we performed a genome-wide association study (GWAS) to identify genomic regions and candidate genes associated with susceptibility to MAP infection in dairy cattle.ResultsUsing Illumina Bovine 50 K (54,609 SNPs) and GeneSeek HD (138,893 SNPs) chips, two analytical approaches were performed, GRAMMAR-GC and ROADTRIPS in 937 Chinese Holstein cows, among which individuals genotyped by the 50 K chip were imputed to HD SNPs with Beagle software. Consequently, 15 and 11 significant SNPs (P < 5 × 10− 5) were identified with GRAMMAR-GC and ROADTDRIPS, respectively. A total of 10 functional genes were in proximity to (i.e., within 1 Mb) these SNPs, including IL4, IL5, IL13, IRF1, MyD88, PACSIN1, DEF6, TDP2, ZAP70 and CSF2. Functional enrichment analysis showed that these genes were involved in immune related pathways, such as interleukin, T cell receptor signaling pathways and inflammatory bowel disease (IBD), implying their potential associations with susceptibility to MAP infection. In addition, by examining the publicly available cattle QTLdb, a previous QTL for MAP was found to be overlapped with one of regions detected currently at 32.5 Mb on BTA23, where the TDP2 gene was anchored.ConclusionsIn conclusion, we identified 26 SNPs located on 15 chromosomes in the Chinese Holstein population using two GWAS strategies with high density SNPs. Integrated analysis of GWAS, biological functions and the reported QTL information helps to detect positional candidate genes and the identification of regions associated with susceptibility to MAP traits in dairy cattle.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5385-3) contains supplementary material, which is available to authorized users.

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“…These individuals suffer from recurrent life-threatening infections, usually early in life, and require hematopoietic cell transplantation to survive (142). Other less common clinical manifestations of ZAP-70 deficiency include skin infiltration with dysfunctional CD4 + T cells (143), elevated serum IgE and eosinophilia (143)(144)(145)(146), diffuse large B cell lymphoma (147), idiopathic thrombocytopenia (148,149), colitis (148,150), congenital nephrotic syndrome, and brain infarcts (151).…”

Section: Severe Combined Immunodeficiencymentioning

confidence: 99%

ZAP-70 in Signaling, Biology, and Disease

Au-Yeung

Shah

Shen

et al. 2018

Annu. Rev. Immunol.

117

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T cells possess an array of functional capabilities important for host defense against pathogens and tumors. T cell effector functions require the T cell antigen receptor (TCR). The TCR has no intrinsic enzymatic activity, and thus signal transduction from the receptor relies on additional signaling molecules. One such molecule is the cytoplasmic tyrosine kinase ZAP-70, which associates with the TCR complex and is required for initiating the canonical biochemical signal pathways downstream of the TCR. In this article, we describe recent structure-based insights into the regulation and substrate specificity of ZAP-70, and then we review novel methods for determining the role of ZAP-70 catalytic activity-dependent and -independent signals in developing and mature T cells. Lastly, we discuss the disease states in mouse models and humans, which range from immunodeficiency to autoimmunity, that are caused by mutations in ZAP-70.

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Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature

Cited by 17 publications

References 36 publications

Lymphocyte Disturbance in The [Asp521Asn] ZAP70 Mutation and An Overview of All Phenotype/Genotype

Lymphocyte Disturbance in The [Asp521Asn] ZAP70 Mutation and An Overview of All Phenotype/Genotype

Genome-wide association study of Mycobacterium avium subspecies Paratuberculosis infection in Chinese Holstein

ZAP-70 in Signaling, Biology, and Disease

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