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

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

  • Blood. 2022 Oct 27;140(17):1858-1874. doi: 10.1182/blood.2022015674.
Mehul Sharma 1 2,  Maggie P Fu 3 4,  Henry Y Lu 1 2,  Ashish A Sharma 5,  Bhavi P Modi 1,  Christina Michalski 1 2,  Susan Lin 1,  Joshua Dalmann 1,  Areesha Salman 1,  Kate L Del Bel 1,  Meriam Waqas 1,  Jefferson Terry 6,  Audi Setiadi 6,  Pascal M Lavoie 1 2,  Wyeth W Wasserman 3 7,  Jill Mwenifumbo 3,  Michael S Kobor 3 4 7,  Anna F Lee 6,  Florian Kuchenbauer 8,  Anna Lehman 3,  Sylvia Cheng 1,  Anthony Cooper 9,  Millan S Patel 3,  Stuart E Turvey 1 2
Affiliations

Affiliations

  • 1 Department of Pediatrics, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.
  • 2 Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
  • 3 Department of Medical Genetics, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, BC, Canada.
  • 4 Genome Science and Technology Program, Faculty of Science, The University of British Columbia, Vancouver, BC, Canada.
  • 5 Department of Pathology, Emory University, Atlanta, GA.
  • 6 Department of Pathology and Laboratory Medicine, BC Children's Hospital, The University of British Columbia, Vancouver, BC, Canada.
  • 7 Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, BC, Canada.
  • 8 Terry Fox Laboratory, BC Cancer Agency, The University of British Columbia, Vancouver, BC, Canada.
  • 9 Department of Orthopaedics, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
PMID: 35789258 DOI: 10.1182/blood.2022015674
Abstract

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.

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