<i>NUDCD3</i> deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome-Reference-Cited by-同舟云学术

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

Published:2024-05-24 Issue:95 Volume:9 Page:
ISSN:2470-9468
Container-title:Science Immunology
language:en
Short-container-title:Sci. Immunol.

Author:

Chen Rui¹^ORCID,Lukianova Elena²^ORCID,van der Loeff Ina Schim¹³^ORCID,Spegarova Jarmila Stremenova¹^ORCID,Willet Joseph D.P.¹,James Kieran D.⁴^ORCID,Ryder Edward J.²^ORCID,Griffin Helen¹^ORCID,IJspeert Hanna⁵,Gajbhiye Akshada⁶^ORCID,Lamoliatte Frederic⁶,Marin-Rubio Jose L.⁶^ORCID,Woodbine Lisa⁷,Lemos Henrique¹,Swan David J.¹,Pintar Valeria¹^ORCID,Sayes Kamal¹,Ruiz-Morales Elias R.²^ORCID,Eastham Simon²,Dixon David⁶^ORCID,Prete Martin²^ORCID,Prigmore Elena²^ORCID,Jeggo Penny⁷,Boyes Joan⁸^ORCID,Mellor Andrew¹^ORCID,Huang Lei¹^ORCID,van der Burg Mirjam⁵^ORCID,Engelhardt Karin R.¹^ORCID,Stray-Pedersen Asbjørg⁹^ORCID,Erichsen Hans Christian¹⁰,Gennery Andrew R.¹³^ORCID,Trost Matthias⁶^ORCID,Adams David J.²^ORCID,Anderson Graham⁴^ORCID,Lorenc Anna²^ORCID,Trynka Gosia²¹¹^ORCID,Hambleton Sophie¹³^ORCID

Affiliation:

1. Translational and Clinical Research Institute, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.

2. Wellcome Sanger Institute, Wellcome Genome Campus, CB10 1SA Hinxton, UK.

3. Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, NE1 4LP Newcastle upon Tyne, UK.

4. Institute of Immunology and Immunotherapy, University of Birmingham. B15 2TT Birmingham, UK.

5. Department of Immunology, Erasmus University Medical Center, Rotterdam 3000 CA, Netherlands.

6. Biosciences Institute, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.

7. Genome Damage and Stability Centre, University of Sussex, BN1 9RQ Brighton, UK.

8. Faculty of Biological Sciences, University of Leeds, LS2 9JT Leeds, UK.

9. Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo 0424, Norway.

10. Division of Pediatric and Adolescent Medicine, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo 0424, Norway.

11. Open Targets, Wellcome Genome Campus, CB10 1SA Hinxton, UK.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciimmunol.ade5705

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