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

The Journal of Experimental Medicine
Alice Y ChanJennifer M Puck

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 autoreact...Continue Reading

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Citations

Apr 12, 2016·Expert Review of Clinical Immunology·Gholamreza AziziAsghar Aghamohammadi
Nov 2, 2016·Expert Review of Clinical Immunology·László Maródi
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Methods Mentioned

BETA
biopsy
electron microscopy
PMA
transfections
transfection
flow cytometry

Software Mentioned

GATK
BWA
CADD
GENEART
SIFT
KING
Varant
Polyphen2
PyMOL

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