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Lookup NU author(s): Dr Rui ChenORCiD, Dr Jarmila SpegarovaORCiD, Dr Joe Willet, Dr Helen GriffinORCiD, Dr Akshada Gajbhiye, Frederic Lamoliatte, Dr Jose Luis Marin-RubioORCiD, Dr David Swan, David Dixon, Emeritus Professor Andrew MellorORCiD, Dr Lei HuangORCiD, Dr Karin Engelhardt, Professor Andrew GenneryORCiD, Professor Matthias TrostORCiD, Professor Sophie Hambleton
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Chen R, Lukianova E, van der Loeff IS, Spegarova JS, Willet JDP, James KD, Ryder EJ, Griffin H, IJspeert H, Gajbhiye A, Lamoliatte F, Marin-Rubio JL, Woodbine L, Lemos H, Swan DJ, Pintar V, Sayes K, Ruiz-Morales ER, Eastham S, Dixon D, Prete M, Prigmore E, Jeggo P, Boyes J, Mellor A, Huang L, van der Burg M, Engelhardt KR, Stray-Pedersen A, Erichsen HC, Gennery AR, Trost M, Adams DJ, Anderson G, Lorenc A, Trynka G, Hambleton S
Publication type: Article
Publication status: Published
Journal: Science Immunology
Year: 2024
Volume: 9
Issue: 95
Online publication date: 24/05/2024
Acceptance date: 23/04/2024
Date deposited: 27/06/2024
ISSN (electronic): 2470-9468
Publisher: American Association for the Advancement of Science (AAAS)
URL: https://doi.org/10.1126/sciimmunol.ade5705
DOI: 10.1126/sciimmunol.ade5705
ePrints DOI: 10.57711/459n-cd96
Data Access Statement: The mouse strain created for this work, on the C57BL/6NTac/USA background, can be obtained from the European Mouse Mutant Archive, accession number 13836 (full allele name: Nudcd3em1(IMPC)Wtsi). All data and code with the exception of patient DNA sequencing data, are included within this paper or are deposited in data repositories. Exome sequencing data are only available to vetted researchers (and not to the broader public) via a data transfer agreement (DTA). The human scRNA sequencing data have been deposited to ArrayExpress with accession number E-MTAB-12283. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (63) partner repository with the dataset identifier PXD035840. The mouse TCR/BCR sequencing data have been deposited to European Nucleotide Archive with the project identifier PRJEB55545. All other data are available in the main text or the supplementary materials.
PubMed id: 38787962
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