ArticleThe Journal of experimental medicine2016
A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.
Article in The Journal of experimental medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 2 of them syntheses that pooled it.
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Who cites it
54 citing papers in PubMed, 2 syntheses or guidelines pooled it, 98 citations in OpenAlex.
- Genome-wide association analyses of autoimmune hypothyroidism reveal autoimmune and thyroid-specific contributions and an inverse relationship with cancer risk.Nature genetics · 2026Pooled it
- Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review.Frontiers in immunology · 2020Pooled it
- Association ofFrontiers in bioinformatics · 2026Article
- Discriminating activating, deactivating and resistance variants in protein kinases.Genome medicine · 2025Article
- First case of primary CNS lymphoma in a patient with severe combined immunodeficiency carrying a novel ZAP70 mutation: a case report.Annals of medicine and surgery (2012) · 2025Article
- Rheumatologic and Autoimmune Features of Inborn Errors of Immunity: Implications for Diagnosis and Management.Journal of human immunity · 2025Article
- The complement factor H-related protein-5 (CFHR5) exacerbates pathological bone formation in ankylosing spondylitis.Journal of molecular medicine (Berlin, Germany) · 2024Article
- ZAP-70 mutation: a case with familial autoimmune haemolytic anaemia and immune deficiency.BMJ case reports · 2024Article
- A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.The Journal of experimental medicine · 2024Article
- Novel Compound Heterozygous ZAP70 R37G A507T Mutations in Infant with Severe Immunodeficiency.Journal of clinical immunology · 2023Article
- The 4-1BBζ costimulatory domain in chimeric antigen receptors enhances CD8+ T-cell functionality following T-cell receptor stimulation.Cancer cell international · 2023Article
- Decoding the deactivation mechanism of R192W mutation of ZAP-70 using molecular dynamics simulations and binding free energy calculations.Journal of molecular modeling · 2023Article
- Pharmacologic Management of Monogenic and Very Early Onset Inflammatory Bowel Diseases.Pharmaceutics · 2023Review
- Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease.The Journal of experimental medicine · 2023Article
- Case Report of a Novel Association between Anti-p200 Pemphigoid and Acquired Haemophilia A.Annals of dermatology · 2023Article
- Combined immunodeficiency caused by pathogenic variants in theFrontiers in immunology · 2023Article
- Novel PGM3 mutation in two siblings with combined immunodeficiency and childhood bullous pemphigoid: a case report and review of the literature.Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology · 2022Article
- A Cysteine Residue within the Kinase Domain of Zap70 Regulates Lck Activity and Proximal TCR Signaling.Cells · 2022Article
- Oral dextran sulfate sodium administration induces peripheral spondyloarthritis features in SKG mice accompanied by intestinal bacterial translocation and systemic Th1 and Th17 cell activation.Arthritis research & therapy · 2022Article
- Linking Genetic Diagnosis to Therapeutic Approach in Very Early Onset Inflammatory Bowel Disease: Pharmacologic Considerations.Paediatric drugs · 2022Review
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Authors and funding
13 authors at 6 institutions in 2 countries.
Funding
Abstract
A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved their autoimmunity. The early onset, severity, and distinctive findings suggested a single gene disorder underlying the phenotype. Whole-exome sequencing performed on five family members revealed the affected siblings to be compound heterozygous for two unique missense mutations in the 70-kD T cell receptor ζ-chain associated protein (ZAP-70). Healthy relatives were heterozygous mutation carriers. Although pre-HCT patient T cells were not available, mutation effects were determined using transfected cell lines and peripheral blood from carriers and controls. Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ζ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein. Although human ZAP-70 deficiency can have dysregulated T cells, and autoreactive mouse thymocytes with weak Zap-70 signaling can escape tolerance, our patients' combination of hypomorphic and activating mutations suggested a new disease mechanism and produced previously undescribed human ZAP-70-associated autoimmune disease.
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