A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis
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.
Authors
- Connie Yang
- Anna F. Lee (ORCID: https://orcid.org/0000-0002-6703-0656)
- Catherine M. Biggs (ORCID: https://orcid.org/0000-0002-4363-2660)
- Marita Bosticardo (ORCID: https://orcid.org/0000-0002-1771-4523)
- Rozita Razavi
- Luigi Daniele Notarangelo (ORCID: https://orcid.org/0000-0002-8335-0262)
- Phillip A. Richmond (ORCID: https://orcid.org/0000-0003-1882-6014)
- Mihai Albu
- Arttu Jolma (ORCID: https://orcid.org/0000-0002-2543-7490)
- Stuart E. Turvey (ORCID: https://orcid.org/0000-0003-1599-1065)
- Kaitlin U. Laverty (ORCID: https://orcid.org/0009-0004-4341-4665)
- Maryam Vaseghi‐Shanjani (ORCID: https://orcid.org/0000-0001-8734-169X)
- YL Lau (ORCID: https://orcid.org/0000-0002-4780-0289)
- Michelle Demos (ORCID: https://orcid.org/0000-0002-3380-0843)
- Liam Golding (ORCID: https://orcid.org/0000-0002-8851-8052)
- Timothy R. Hughes (ORCID: https://orcid.org/0000-0002-8721-4719)
- Mehul Sharma (ORCID: https://orcid.org/0000-0002-9591-0415)
- Ally Yang (ORCID: https://orcid.org/0000-0002-8678-0946)
- Kyla J. Hildebrand (ORCID: https://orcid.org/0000-0003-3825-8202)
- Rae Brager (ORCID: https://orcid.org/0000-0002-0038-9699)
- Simran Samra (ORCID: https://orcid.org/0000-0002-8026-3139)
- Pariya Yousefi (ORCID: https://orcid.org/0009-0005-6306-6204)
- Jonathan H. Rayment (ORCID: https://orcid.org/0000-0003-4955-8876)
- Ryan Tan (ORCID: https://orcid.org/0000-0001-6733-9920)
Institutions
- National Institutes of Health (US)
- University of British Columbia (CA)
- University of Toronto (CA)
- Queen Mary Hospital (CN)
- McMaster Children's Hospital (CA)
- Donnelly College (US)
- National Institute of Allergy and Infectious Diseases (US)
- BC Children's Hospital (CA)
- University of Hong Kong (HK)
- McMaster University (CA)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-03-29
- DOI
- https://doi.org/10.1084/jem.20241174
- Citations
- 1
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- BC Children’s Hospital Foundation
- Michael Smith Health Research BC
- Genome British Columbia
- Canadian Institutes of Health Research