Inherited human TFIIIA deficiency disrupts T cell development
Year: 2026
Type: preprint
Abstract: ABSTRACT Molecular characterization of human monogenic inborn errors of T cell immunity provides both biological insights and medical progress. We report rare biallelic deleterious variants in GTF3A , encoding transcription factor IIIA (TFIIIA), a zinc-finger protein required for transcription and chaperoning of 5S ribosomal RNA (rRNA). These variants were identified in ten patients from eight unrelated families and eight countries presenting with either T - B + NK + severe combined immunodeficiency (SCID) or combined immune deficiency (CID), characterized by T cell lymphopenia and variable antibody deficiency. The GTF3A variants disrupt TFIIIA function through distinct mechanisms, including defective DNA binding, aberrant nuclear localization, and reduced protein stability compromising TFIIIA-mediated transcription and chaperoning of 5S rRNA. Using artificial thymic organoids derived from TFIIIA-deficient CD34⁺ progenitors, an early developmental arrest at the T cell commitment stage was documented in vitro . Zebrafish deficient for gtf3aa recapitulated the impaired thymocyte development in vivo . Together, these findings establish TFIIIA deficiency as a novel cause of (S)CID, expanding the genetic and mechanistic landscape of inborn errors of T cell immunity and uncovering an essential role for TFIIIA in human adaptive immunity. One-sentence summary Biallelic GTF3A variants causing TFIIIA deficiency, which disrupts 5S rRNA transcription, represent a novel monogenic cause of (S)CID, unveiling a crucial role of TFIIIA in T cell development.
Source: medRxiv
Authors: Evi Duthoo, Sueun Park, Tamara Jarayseh, Marita Bosticardo, Rafah Mackeh, Yana Van Droogenbroeck, Imke Velghe, Veronique Debacker, Hailun Li, Nourhen Agrebi, Francesca Pala, Sarah Ghistelinck, Julie Braet, Sandra Van Lint, Lukas Pieters, Martin Watelet, Hajar Besbassi, Leslie Naesens, Tessa Kerre, Delfien Bogaert, Hye Sun Kuehn, Sergio D. Rosenzweig, Emmanuelle Jouanguy, Ottavia M. Delmonte, Ivan K. Chinn, Stephen Hughes, Amel Hassan, Mohammed Y. Karim, Asha Elmi, Giuliana Giardino, Claudio Pignata, Bénédicte Neven, Benson Ogunjimi, Karim Vermaelen, Denis L.J. Lafontaine, Mirjam van der Burg, Anne Puel, Jérémie Rosain, Jean-Laurent Casanova, Bernice Lo, Patrick Sips, Tom Taghon, Jacinta Bustamante, Luigi D. Notarangelo, Simon J. Tavernier, Filomeen Haerynck
Institutions: Ghent University Hospital, Ghent University, Cancer Research Institute Ghent, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Sidra Medical and Research Center, Hôpital Necker-Enfants Malades, Inserm, Université Paris Cité, Human Genetic of Infectious Diseases, Institut des Maladies Génétiques Imagine, University of Antwerp, Children's Health Ireland at Crumlin, National Institutes of Health Clinical Center, Rockefeller University, Baylor College of Medicine, Texas Children's Hospital, Royal Manchester Children's Hospital, Qatar University, Federico II University Hospital, University of Naples Federico II, Assistance Publique – Hôpitaux de Paris, Antwerp University Hospital, Université Libre de Bruxelles, Fund for Scientific Research, Leiden University Medical Center, Howard Hughes Medical Institute, Hamad bin Khalifa University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7166865573