title: A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70.
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.
authors.affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94143.
authors.forename: Alice Y
authors.initials: AY
authors.lastname: Chan
authors.affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94143.
authors.forename: Divya
authors.initials: D
authors.lastname: Punwani
authors.affiliation: 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.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Kadlecek
authors.affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94143.
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
authors.affiliation: Department of Pathology, University of California San Francisco School of Medicine, San Francisco, CA 94143.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Olson
authors.affiliation: 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.
authors.forename: Erin F
authors.initials: EF
authors.lastname: Mathes
authors.affiliation: Innovation Labs, Tata Consulting Services, Hyderabad 50019, Telangana, India.
authors.forename: Uma
authors.initials: U
authors.lastname: Sunderam
authors.affiliation: Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908.
authors.forename: Shu Man
authors.initials: SM
authors.lastname: Fu
authors.affiliation: Innovation Labs, Tata Consulting Services, Hyderabad 50019, Telangana, India.
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Srinivasan
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Brenner
authors.affiliation: 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.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA 94143 jennifer.puck@ucsf.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D002460:Cell Line; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006467:Hemophilia A / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D010391:Pemphigoid, Bullous / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D035781:Siblings; D013577:Syndrome; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D014184:Transplantation, Homologous; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human