Journal
BLOOD
Volume 140, Issue 17, Pages 1858-1874Publisher
AMER SOC HEMATOLOGY
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Funding
- Canadian Institutes of Health Research [PJT 178054]
- Genome British Columbia [SIP007]
- BC Children's Hospital Foundation
- Tier 1 Canada Research Chair in Pediatric Precision Health
- CIHR Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (CGS-D)
- University of British Columbia Four Year Doctoral Fellowship (4YF)
- CGS-D, 4YF, Killam Doctoral Scholarship, Friedman Award for Scholars in Health
- BC Children's Hospital Research Institute Graduate Studentship
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The discovery of a human patient with complete deficiency of NFAT1 provides new insights into the pleiotropic role of NFAT1 and the detrimental effects associated with long-term use of calcineurin inhibitors.
The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023_2026delTACC; p.Tyr675Thrfs*18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naive B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors.
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