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
  • 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.