| First Author | Chen R | Year | 2024 |
| Journal | Sci Immunol | Volume | 9 |
| Issue | 95 | Pages | eade5705 |
| PubMed ID | 38787962 | Mgi Jnum | J:351330 |
| Mgi Id | MGI:7663049 | Doi | 10.1126/sciimmunol.ade5705 |
| Citation | Chen R, et al. (2024) NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome. Sci Immunol 9(95):eade5705 |
| abstractText | 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. |
