Novel Compound Heterozygous ZAP70 R37G A507T Mutations in Infant with Severe Immunodeficiency.

Autor: Benavides N; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA., White JC; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA.; Department of Pediatric Hematology/Oncology, Nemours Children's Hospital Delaware, Wilmington, USA., Sanmillan ML; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA., Thomas M; Department of Genetics, Nemours Children's Hospital Delaware, Wilmington, USA., Le T; Department of Allergy/Immunology, Nemours Children's Hospital Delaware, Wilmington, USA., Caywood E; Department of Pediatric Hematology/Oncology, Nemours Children's Hospital Delaware, Wilmington, USA., Giraudo CG; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA. Claudio.Giraudo@jefferson.edu.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2023 Dec 22; Vol. 44 (1), pp. 27. Date of Electronic Publication: 2023 Dec 22.
DOI: 10.1007/s10875-023-01608-2
Abstrakt: Zeta-chain associated protein kinase 70 kDa (ZAP70) combined immunodeficiency (CID) is an autosomal recessive severe immunodeficiency that is characterized by abnormal T-cell receptor signaling. Children with the disorder typically present during the first year of life with diarrhea, failure to thrive, and recurrent bacterial, viral, or opportunistic infections. To date, the only potential cure is hematopoietic stem cell transplant (HSCT). The majority of described mutations causing disease occur in the homozygous state, though heterozygotes are reported without a clear understanding as to how the individual mutations interact to cause disease. This case describes an infant with novel ZAP-70 deficiency mutations involving the SH2 and kinase domains cured with allogeneic HSCT utilizing a reduced-intensity conditioning regimen and graft manipulation. We then were able to further elucidate the molecular signaling alterations imparted by these mutations that lead to altered immune function. In order to examine the effect of these novel compound ZAP70 heterozygous mutations on T cells, Jurkat CD4 + T cells were transfected with either wild type, or with individual ZAP70 R37G and A507T mutant constructs. Downstream TCR signaling events and protein localization results link these novel mutations to the expected immunological outcome as seen in the patient's primary cells. This study further characterizes mutations in the ZAP70 gene as combined immunodeficiency and the clinical phenotype.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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