Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy.

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 naïve 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. © 2022 by The American Society of Hematology.

Citation

Mehul Sharma, Maggie P Fu, Henry Y Lu, Ashish A Sharma, Bhavi P Modi, Christina Michalski, Susan Lin, Joshua Dalmann, Areesha Salman, Kate L Del Bel, Meriam Waqas, Jefferson Terry, Audi Setiadi, Pascal M Lavoie, Wyeth W Wasserman, Jill Mwenifumbo, Michael S Kobor, Anna F Lee, Florian Kuchenbauer, Anna Lehman, Sylvia Cheng, Anthony Cooper, Millan S Patel, Stuart E Turvey. Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy. Blood. 2022 Oct 27;140(17):1858-1874

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PMID: 35789258

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