| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q11.2 | Autoimmune disease, multisystem, infantile-onset, 2 | 617006 | Autosomal recessive | 3 | ZAP70 | 176947 |
A number sign (#) is used with this entry because of evidence that infantile-onset multisystem autoimmune disease-2 (ADMIO2) is caused by compound heterozygous mutation in the ZAP70 gene (176947) on chromosome 2q12. One such family has been reported.
For a discussion of genetic heterogeneity of ADMIO, see ADMIO1 (615952).
Chan et al. (2016) reported a brother and sister, born of unrelated Caucasian parents, with onset of a systemic autoimmune disorder in the first months of life. The boy developed nephrotic syndrome at age 9 months, and renal biopsy showed mild IgG deposition with widespread foot process effacement consistent with minimal change disease. By age 20 months, he developed blistering skin disease, and biopsy showed bullous pemphigoid, with subepidermal clefting, infiltration with eosinophils and neutrophils, and IgG deposition at the basement membrane and intercellularly. He developed bleeding due to F8 (300841) autoantibodies at age 2 and inflammatory colitis at age 3. His autoimmune disease became refractory to high-dose steroids and multiple immunosuppressive regimens. His sister developed bullous pemphigoid at 1 month of age, followed by inflammatory colitis, proteinuria in the absence of nephrotic syndrome, and autoimmune hypothyroidism. Neither child had recurrent infections. Immunologic workup showed mild T and B cell lymphopenia and reduced numbers of CD8+ T cells. Both patients also had a decreased T-cell proliferative responses. Both patients underwent hematopoietic stem cell transplant, resulting in complete resolution of the disorder.
The transmission pattern of ADMIO2 in the family reported by Chan et al. (2016) was consistent with autosomal recessive inheritance.
In 2 sibs with ADMIO2, Chan et al. (2016) identified compound heterozygous missense mutations in the ZAP70 gene (R192W, 176947.0006 and R360P, 176947.0007). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Studies of transfected cell lines and cells from the carrier parents showed that the R192W was a hypomorphic allele with reduced binding to phosphorylated T cell receptor (TCR) zeta-chain (CD247; 186780), whereas R360P was weakly hyperactive compared to wildtype, most likely due to disruption of the autoinhibitory mechanism. The combination of hypomorphic and activating mutations suggested a novel disease mechanism, resulting in a theretofore undescribed human ZAP70-associated autoimmune disease.
Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., Sunderam, U., Fu, S. M., Srinivasan, R., Kuriyan, J., Brenner, S. E., Weiss, A., Puck, J. M. A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J. Exp. Med. 213: 155-165, 2016. [PubMed: 26783323] [Full Text: https://doi.org/10.1084/jem.20150888]