| Autor: |
Chen, Rui, Lukianova, Elena, van der Loeff, Ina Schim, Spegarova, Jarmila Stremenova, Willet, Joseph D.P., James, Kieran D., Ryder, Edward J., Griffin, Helen, IJspeert, Hanna, Gajbhiye, Akshada, Lamoliatte, Frederic, Marin-Rubio, Jose L., Woodbine, Lisa, Lemos, Henrique, Swan, David J., Pintar, Valeria, Sayes, Kamal, Ruiz-Morales, Elias R., Eastham, Simon, Dixon, David |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 95, p1-17, 17p |
| Abstrakt: |
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. Editor's summary: Severe combined immunodeficiency (SCID) and Omenn syndrome (OS) are two related inborn errors of immunity that continue to inform our understanding of how human lymphocytes develop. Chen et al. report the existence of 11 patients with SCID or OS who have a single homozygous deleterious missense variant (G52D) of the gene NUDCD3. These NUDCD3G52D patients showed defects in RAG-mediated V(D)J recombination, a critical step in B and T cell development, namely, the pathological sequestration of RAG1 in the nucleoli and reduced recombinase activity. Mice with a knock-in Nudcd3G52D variant also exhibited altered B and T cell development but to a lesser degree than in the human patients or in other RAG-deficient mouse models. These findings suggest that NUDCD3 may be an important cochaperone in RAG2-mediated egress of RAG1 from the nucleoli. —Seth Thomas Scanlon [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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