2. Academic Validation
  3. A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis

A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis

  • J Exp Med. 2025 Aug 4;222(8):e20241174. doi: 10.1084/jem.20241174.
Maryam Vaseghi-Shanjani # 1 2,  Mehul Sharma # 2,  Pariya Yousefi 2,  Simran Samra 1 2,  Kaitlin U Laverty 3,  Arttu Jolma 3,  Rozita Razavi 3,  Ally H W Yang 3,  Mihai Albu 3,  Liam Golding 2,  Anna F Lee 4,  Ryan Tan 2,  Phillip A Richmond 5,  Marita Bosticardo 6,  Jonathan H Rayment 2,  Connie L Yang 2,  Kyla J Hildebrand 2,  Rae Brager 7,  Michelle K Demos 2,  Yu-Lung Lau 8,  Luigi D Notarangelo 6,  Timothy R Hughes 9,  Catherine M Biggs # 2,  Stuart E Turvey # 2
Affiliations

Affiliations

  • 1 Experimental Medicine Program, Faculty of Medicine, The University of British Columbia , Vancouver, Canada.
  • 2 Department of Pediatrics, BC Children's Hospital, The University of British Columbia, Vancouver, Canada.
  • 3 Donnelly Centre, University of Toronto , Toronto, Canada.
  • 4 Department of Pathology and Laboratory Medicine, BC Children's Hospital, The University of British Columbia, Vancouver, Canada.
  • 5 The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, The University of British Columbia, BC Children's Hospital , Vancouver, Canada.
  • 6 Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, USA.
  • 7 Division of Rheumatology, Immunology, and Allergy, Department of Paediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
  • 8 Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, Canada.
  • # Contributed equally.
PMID: 40392549 DOI: 10.1084/jem.20241174
Abstract

ThPOK is a transcription factor that acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by a genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2:c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA Sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, the transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation and ThPOKK360N-transduced fibroblasts with increased profibrotic gene expression. This novel human disease confirms ThPOK's role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.

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