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J Exp Med. 2016 Feb 8;213(2):155-65. doi: 10.1084/jem.20150888. Epub 2016 Jan 18.

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

Author information

1
Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94143.
2
Department of Medicine, Rosalind Russell and Ephraim Engleman Rheumatology Research Center and Howard Hughes Medical Institute, University of California San Francisco School of Medicine, San Francisco, CA 94143.
3
Department of Pathology, University of California San Francisco School of Medicine, San Francisco, CA 94143.
4
Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94143 Department of Dermatology, University of California San Francisco School of Medicine, San Francisco, CA 94143.
5
Innovation Labs, Tata Consulting Services, Hyderabad 50019, Telangana, India.
6
Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908.
7
Department of Molecular and Cell Biology and Department of Chemistry, California Institute of Quantitative Biosciences and Howard Hughes Medical Institute and Physical Biosciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, Berkeley, CA 94720.
8
Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720.
9
Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94143 jennifer.puck@ucsf.edu.

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.

PMID:
26783323
PMCID:
PMC4749924
DOI:
10.1084/jem.20150888
[Indexed for MEDLINE]
Free PMC Article

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