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

ABSTRACT: Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 9 affected patients across 3 consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain containing 3 (NUDCD3). Two infants lacked T and B lymphocytes altogether (T-B- severe combined immunodeficiency, T-B- SCID) while 7 showed classical features of Omenn syndrome. Restricted antigen receptor gene usage by residual T lymphocytes implied impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, associated with pathologic sequestration of RAG1 in nucleoli. A mouse model bearing the homologous variant phenocopied these abnormalities, confirming a conserved, requisite role for NUDCD3 in V(D)J recombination.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, T Cell

SUBMITTER: Matthias Trost  

LAB HEAD: Matthias Trost

PROVIDER: PXD035840 | Pride | 2024-09-27

REPOSITORIES: Pride