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Lookup NU author(s): Dr Rui ChenORCiD, Dr Ina Schim van der LoeffORCiD, Dr Jarmila SpegarovaORCiD, Dr Joe Willet, Dr Helen GriffinORCiD, Dr Akshada Gajbhiye, Dr 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
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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
Print publication date: 01/05/2024
Online publication date: 24/05/2024
Acceptance date: 24/04/2024
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
PubMed id: 38787962
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