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Published on: January 7, 2019
NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome
Rui Chen1, Elena Lukianova2, Ina Schim van der Loeff1,3
1Translational and Clinical Research Institute, Newcastle University, NE2 4HH Newcastle upon Tyne, 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.
Insights
Genetic defects in NUDC domain-containing 3 (NUDCD3) cause severe combined immunodeficiency (SCID) and Omenn syndrome in infants. This highlights NUDCD3
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Inborn errors of T cell development are pediatric emergencies requiring molecular diagnosis for timely treatment.
- Severe combined immunodeficiency (SCID) and Omenn syndrome (OS) represent critical conditions affecting T cell development.
Purpose of the Study:
- To identify the genetic cause of severe immunodeficiency in infants presenting with SCID or OS.
- To elucidate the molecular mechanism by which the identified genetic defect impairs T cell development.
Main Methods:
- Whole-exome sequencing was performed on affected patients from consanguineous kindreds.
- Immunological assays and in vitro recombination assays were used to assess T cell function and V(D)J recombination.
- A mouse model was utilized to study the in vivo effects of the identified genetic variant.
Main Results:
- Homozygosity for a deleterious missense variant in NUDCD3 was identified in 11 patients.
- Patients exhibited either T- B- SCID or Omenn syndrome, with impaired V(D)J recombination.
- NUDCD3 deficiency led to reduced protein expression, impaired RAG-mediated recombination, and RAG1 sequestration in nucleoli.
Conclusions:
- Mutations in NUDCD3 are a novel cause of severe T cell immunodeficiency in humans.
- NUDCD3 is essential for V(D)J recombination and normal T and B cell development.
- Understanding NUDCD3's role provides insights into SCID and OS pathogenesis.
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