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

Chen, R.; Lukianova, E.; Loeff, I.S. van der; Spegarova, J.S.; Willet, J.D.P.; James, K.D.; Ryder, E.J.; Griffin, H.; Ijspeert, H.; Gajbhiye, A.; Lamoliatte, F.; Marin-Rubio, J.L.; Woodbine, L.; Lemos, H.; Swan, D.J.; Pintar, V.; Sayes, K.; Ruiz-Morales, E.R.; Eastham, S.; Dixon, D.; Prete, M.; Prigmore, E.; Jeggo, P.; Boyes, J.; Mellor, A.; Huang, L.; Burg, M. van der; Engelhardt, K.R.; Stray-Pedersen, A.; Erichsen, H.C.; Gennery, A.R.; Trost, M.; Adams, D.J.; Anderson, G.; Lorenc, A.; Trynka, G.; Hambleton, S.

doi:doi:10.1126/sciimmunol.ade5705

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