%0 Journal Article
%T NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome.
%A Chen R
%A Lukianova E
%A van der Loeff IS
%A Spegarova JS
%A Willet JDP
%A James KD
%A Ryder EJ
%A Griffin H
%A IJspeert H
%A Gajbhiye A
%A Lamoliatte F
%A Marin-Rubio JL
%A Woodbine L
%A Lemos H
%A Swan DJ
%A Pintar V
%A Sayes K
%A Ruiz-Morales ER
%A Eastham S
%A Dixon D
%A Prete M
%A Prigmore E
%A Jeggo P
%A Boyes J
%A Mellor A
%A Huang L
%A van der Burg M
%A Engelhardt KR
%A Stray-Pedersen A
%A Erichsen HC
%A Gennery AR
%A Trost M
%A Adams DJ
%A Anderson G
%A Lorenc A
%A Trynka G
%A Hambleton S
%J Sci Immunol
%V 9
%N 95
%D 2024 May 24
%M 38787962
%F 30.63
%R 10.1126/sciimmunol.ade5705
%X 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.