Chen, R. orcid.org/0000-0003-2887-2751, Lukianova, E. orcid.org/0000-0003-3566-5873, van der Loeff, I.S. orcid.org/0000-0003-1196-6196 et al. (34 more authors) (2024) NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome. Science Immunology, 9 (95). eade5705. ISSN 2470-9468
Abstract
Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain–containing 3 (NUDCD3). Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T -B- SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This item is protected by copyright. This is an author produced version of an article published in Science Immunology, made available under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Molecular & Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Jun 2024 09:15 |
Last Modified: | 03 Jun 2024 09:15 |
Status: | Published |
Publisher: | American Association for the Advancement of Science |
Identification Number: | 10.1126/sciimmunol.ade5705 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:213023 |