NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome.

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.

Citation

Rui Chen, Elena Lukianova, Ina Schim van der Loeff, Jarmila Stremenova Spegarova, Joseph D P Willet, Kieran D James, Edward J Ryder, Helen Griffin, Hanna IJspeert, Akshada Gajbhiye, Frederic Lamoliatte, Jose L Marin-Rubio, Lisa Woodbine, Henrique Lemos, David J Swan, Valeria Pintar, Kamal Sayes, Elias R Ruiz-Morales, Simon Eastham, David Dixon, Martin Prete, Elena Prigmore, Penny Jeggo, Joan Boyes, Andrew Mellor, Lei Huang, Mirjam van der Burg, Karin R Engelhardt, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Andrew R Gennery, Matthias Trost, David J Adams, Graham Anderson, Anna Lorenc, Gosia Trynka, Sophie Hambleton. NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome. Science immunology. 2024 May 24;9(95):eade5705

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PMID: 38787962

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