skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70

Journal Article · · Journal of Experimental Medicine
DOI:https://doi.org/10.1084/jem.20150888· OSTI ID:1625200
 [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [2];  [4];  [5];  [1];  [1]
  1. University of California, San Francisco, CA (United States)
  2. Tata Consulting Services, Telangana (India)
  3. University of Virginia, Charlottesville, VA (United States)
  4. Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Howard Hughes Medical Institute, Berkeley, CA (United States)
  5. University of California, Berkeley, CA (United States)
+ Show Author Affiliations

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH); Celera Corporation; Lisa and Douglas Goldman Foundation; University of California San Francisco; Howard Hughes Medical Institute
Grant/Contract Number:
AC02-05CH11231; AI105776; AI078248; NCATS TL1TR000144; P01 AI091580; U54 AI082973
OSTI ID:
1625200
Journal Information:
Journal of Experimental Medicine, Vol. 213, Issue 2; ISSN 0022-1007
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

References (56)

Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease journal July 2014
Redundant role for Zap70 in B cell development and activation journal May 2008
ζ Chain–associated protein of 70 kDa (ZAP70) deficiency in human subjects is associated with abnormalities of thymic stromal cells: Implications for T-cell tolerance journal February 2013
An integrated map of genetic variation from 1,092 human genomes text January 2012
Bullous pemphigoid in infancy: Clinical and epidemiologic characteristics journal January 2008
Nijmegen Breakage Syndrome Detected By Newborn Screening for T Cell Receptor Excision Circles (TRECs) journal February 2015
Differential Requirement of ZAP-70 for CD2-Mediated Activation Pathways of Mature Human T Cells journal October 2000
Nijmegen Breakage Syndrome Detected by Newborn Screening for T Cell Receptor Excision Circles (TRECs) journal February 2015
A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity journal October 2010
T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity journal May 2015
Opposing Functions of the T Cell Receptor Kinase ZAP-70 in Immunity and Tolerance Differentially Titrate in Response to Nucleotide Substitutions journal December 2007
Distinct T Cell Developmental Consequences in Humans and Mice Expressing Identical Mutations in the DLAARN Motif of ZAP-70 journal January 2001
A Diacylglycerol-Protein Kinase C-RasGRP1 Pathway Directs Ras Activation upon Antigen Receptor Stimulation of T Cells journal June 2005
Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind journal February 2015
T‐cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man journal March 2012
Immunological reconstitution in a patient with ZAP-70 deficiency following transfusion of blood lymphocytes from a previously transplanted sibling without conditioning journal March 2011
Silent brain infarcts in two patients with zeta chain-associated protein 70kDa (ZAP70) deficiency journal May 2015
The Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations journal October 2010
Diffuse large B-cell lymphoma as presenting feature of Zap-70 deficiency journal February 2011
Temperature-sensitive ZAP70 Mutants Degrading through a Proteasome-independent Pathway: RESTORATION OF A KINASE DOMAIN MUTANT BY Cdc37 journal December 1999
Characterization of ζ-associated protein, 70 kd (ZAP70)–deficient human lymphocytes journal December 2010
A method and server for predicting damaging missense mutations journal April 2010
Identification of a novel mutation in ZAP70 and prenatal diagnosis in a Turkish family with severe combined immunodeficiency disorder journal January 2013
Mapping the genetic basis of diabetes mellitus in the Australian Burmese cat (Felis catus) journal November 2020
Defective T cell receptor signaling and CD8+ thymic selection in humans lacking Zap-70 kinase journal March 1994
A general framework for estimating the relative pathogenicity of human genetic variants journal February 2014
T cell receptor dwell times control the kinase activity of Zap70 journal August 2015
Limitation of TREC-based newborn screening for ZAP70 Severe Combined Immunodeficiency journal July 2014
Immunodeficiency and immune dysregulation associated with proximal defects of T cell receptor signaling journal December 2014
Graded Attenuation of TCR Signaling Elicits Distinct Autoimmune Diseases by Altering Thymic T Cell Selection and Regulatory T Cell Function journal July 2010
Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity: Clinical immunology journal June 2009
Protein Tyrosine Phosphatase CD148-Mediated Inhibition of T-Cell Receptor Signal Transduction Is Associated with Reduced LAT and Phospholipase Cγ1 Phosphorylation journal April 2001
Structural Basis for the Inhibition of Tyrosine Kinase Activity of ZAP-70 journal May 2007
Transcriptional activation by tetracyclines in mammalian cells journal June 1995
Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency journal May 2008
ZAP70: a master regulator of adaptive immunity journal February 2010
Existence of activated and memory CD4+ T cells in peripheral blood and their skin infiltration in CD8 deficiency journal December 2001
The 22q11.2 Deletion Syndrome: A Gene Dosage Perspective journal January 2006
Journal Info Home About the Journal Editorial Board Archive Research Topics View Some Authors Review Guidelines Subscribe to Alerts Search Article Type Publication Date ...... Go Author Info Why Submit? Fees Article Types Author Guidelines Submission Checklist Contact Editorial Office Submit Manuscript Original Research ARTICLE Abstract PDF 0 Write a Comment “What am I Going to Say Here?” The Experiences of Doctors and Nurses Communicating with Patients in a Cancer Unit journal January 2011
A mutation inzap-70 protein tyrosine kinase results in a selective immunodeficiency journal November 1995
Robust relationship inference in genome-wide association studies journal October 2010
Involvement of p21ras activation in T cell CD69 expression journal March 1994
Predicting Deleterious Amino Acid Substitutions journal May 2001
Chromosome 22q11.2 Deletion Syndrome: DiGeorge Syndrome/Velocardiofacial Syndrome journal May 2008
The 22q11.2 Deletion Syndrome: A gene dosage perspective. journal May 2006
Journal Info Home About the Journal Editorial Board Archive Research Topics View Some Authors Review Guidelines Subscribe to Alerts Search Article Type Publication Date ...... Go Author Info Why Submit? Fees Article Types Author Guidelines Submission Checklist Contact Editorial Office Submit Manuscript Review ARTICLE Abstract Full Text PDF 0 Write a Comment Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency journal January 2011
ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency journal June 1994
Interaction between the SH2 Domains of ZAP-70 and the Tyrosine-Based Activation Motif 1 Sequence of the ζ Subunit of the T-Cell Receptor journal June 1997
Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase journal June 1994
Chromosome 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome) journal January 2011
The structure, regulation, and function of ZAP-70 journal March 2009
Structural Basis for Activation of ZAP-70 by Phosphorylation of the SH2-Kinase Linker journal March 2013
Genetic Evidence for Differential Coupling of Syk Family Kinases to the T-Cell Receptor: Reconstitution Studies in a ZAP-70-Deficient Jurkat T-Cell Line journal March 1998
Intramolecular Regulatory Switch in ZAP-70: Analogy with Receptor Tyrosine Kinases journal June 2005
Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8 journal September 2021
Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency journal April 2014

Cited By (11)

Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation journal November 2017
Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness journal February 2017
Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives journal August 2019
Loss of MafA and MafB expression promotes islet inflammation journal June 2019
Thymic tolerance as a key brake on autoimmunity journal June 2018
Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis journal January 2020
Recent advance in very early-onset inflammatory bowel disease journal January 2019
Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency journal July 2016
Recent advances in primary immunodeficiency: from molecular diagnosis to treatment journal March 2020
ZAP-70 Shapes the Immune Microenvironment in B Cell Malignancies journal October 2020
Recent Advance in Very Early Onset Inflammatory Bowel Disease journal January 2019

Similar Records

Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen
Journal Article · Tue Dec 13 00:00:00 EST 2016 · SLAS DISCOVERY: Advancing Life Sciences R&D · OSTI ID:1625200
+5 more
Suppressor cell function is preserved in pemphigus and pemphigoid
Journal Article · Wed Sep 01 00:00:00 EDT 1982 · J. Invest. Dermatol.; (United States) · OSTI ID:1625200
+2 more
A novel ADCK4 mutation in a Chinese family with ADCK4-Associated glomerulopathy
Journal Article · Thu Nov 15 00:00:00 EST 2018 · Biochemical and Biophysical Research Communications · OSTI ID:1625200

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
combined immunodeficiency
hematopoietic cell transplantation
ζ-chain associated protein 70-kD T cell receptor