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

摘要: A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year life, with uncontrollable bullous pemphigoid, colitis, proteinuria. The boy had hemophilia due to factor VIII autoantibody nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (HCT), which resolved autoimmunity. early onset, severity, distinctive findings suggested single gene disorder underlying the phenotype. Whole-exome sequencing performed on five family members revealed affected siblings be compound heterozygous for two unique missense mutations in 70-kD T receptor ζ-chain associated protein (ZAP-70). Healthy relatives were mutation carriers. Although pre-HCT patient cells not available, effects determined using transfected lines peripheral blood from carriers controls. Mutation R192W C-SH2 domain exhibited reduced binding phosphorylated ζ-chain, whereas R360P N lobe catalytic disrupted an autoinhibitory mechanism, producing weakly hyperactive ZAP-70 protein. human deficiency can have dysregulated cells, autoreactive mouse thymocytes weak Zap-70 signaling escape tolerance, our patients' combination hypomorphic activating new disease mechanism produced ZAP-70-associated disease.