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

Rui Chen; Elena Lukianova; Ina Schim van der Loeff; Jarmila Stremenova Spegarova; Joseph D.P. Willet; Kieran D James; Edward Ryder; Hanna IJspeert; Akshada Gajbhiye; Frederic Lamoliatte; José Luis Marín-Rubio; Lisa Woodbine; Henrique Lemos; David J. Swan; Valeria Pintar; Kamal Sayes; Elias Rafael Ruiz-Morales; Simon Eastham; David Dixon; Martin Prete; Elena Prigmore; Penny Jeggo; Joan Boyes; Andrew Mellor; lei huang; Mirjam van der Burg; Karin Regine Engelhardt; Asbjørg Stray-Pedersen; Hans Christian Erichsen; Andrew Gennery; Matthias Trost; graham anderson; Anna Lorenc; Gosia Trynka; Sophie Hambleton

doi:10.1126/sciimmunol.ade5705

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

Rui Chen, Elena Lukianova, Ina Schim van der Loeff, Jarmila Stremenova Spegarova, Joseph D.P. Willet, Kieran D James, Edward Ryder, Hanna IJspeert, Akshada Gajbhiye, Frederic Lamoliatte, José Luis Marín-Rubio, Lisa Woodbine, Henrique Lemos, David J. Swan, Valeria Pintar, Kamal Sayes, Elias Rafael Ruiz-Morales, Simon Eastham, David Dixon, Martin PreteElena Prigmore, Penny Jeggo, Joan Boyes, Andrew Mellor, lei huang, Mirjam van der Burg, Karin Regine Engelhardt, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Andrew Gennery, Matthias Trost, graham anderson, Anna Lorenc, Gosia Trynka, Sophie Hambleton^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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.

Original language	English
Article number	eade5705
Pages (from-to)	eade5705
Journal	Science Immunology
Volume	9
Issue number	95
DOIs	https://doi.org/10.1126/sciimmunol.ade5705
Publication status	Published - 24 May 2024

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Copyright © 2024 The Authors, some rights reserved;

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Chen, R., Lukianova, E., Loeff, I. S. V. D., Spegarova, J. S., Willet, J. D. P., James, K. D., Ryder, E., IJspeert, H., Gajbhiye, A., Lamoliatte, F., Marín-Rubio, J. L., Woodbine, L., Lemos, H., Swan, D. J., Pintar, V., Sayes, K., Ruiz-Morales, E. R., Eastham, S., Dixon, D., ... Hambleton, S. (2024). NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome. Science Immunology, 9(95), eade5705. Article eade5705. https://doi.org/10.1126/sciimmunol.ade5705

@article{418c6191c01a47daa6248aea3bba3497,

title = "NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome",

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.",

author = "Rui Chen and Elena Lukianova and Loeff, {Ina Schim van der} and Spegarova, {Jarmila Stremenova} and Willet, {Joseph D.P.} and James, {Kieran D} and Edward Ryder and Hanna IJspeert and Akshada Gajbhiye and Frederic Lamoliatte and Mar{\'i}n-Rubio, {Jos{\'e} Luis} and Lisa Woodbine and Henrique Lemos and Swan, {David J.} and Valeria Pintar and Kamal Sayes and Ruiz-Morales, {Elias Rafael} and Simon Eastham and David Dixon and Martin Prete and Elena Prigmore and Penny Jeggo and Joan Boyes and Andrew Mellor and lei huang and Burg, {Mirjam van der} and Engelhardt, {Karin Regine} and Asbj{\o}rg Stray-Pedersen and Erichsen, {Hans Christian} and Andrew Gennery and Matthias Trost and graham anderson and Anna Lorenc and Gosia Trynka and Sophie Hambleton",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 The Authors, some rights reserved;",

year = "2024",

month = may,

day = "24",

doi = "10.1126/sciimmunol.ade5705",

language = "English",

volume = "9",

pages = "eade5705",

journal = "Science Immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

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Chen, R, Lukianova, E, Loeff, ISVD, Spegarova, JS, Willet, JDP, James, KD, Ryder, E, IJspeert, H, Gajbhiye, A, Lamoliatte, F, Marín-Rubio, JL, Woodbine, L, Lemos, H, Swan, DJ, Pintar, V, Sayes, K, Ruiz-Morales, ER, Eastham, S, Dixon, D, Prete, M, Prigmore, E, Jeggo, P, Boyes, J, Mellor, A, huang, L, Burg, MVD, Engelhardt, KR, Stray-Pedersen, A, Erichsen, HC, Gennery, A, Trost, M, anderson, G, Lorenc, A, Trynka, G & Hambleton, S 2024, 'NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome', Science Immunology, vol. 9, no. 95, eade5705, pp. eade5705. https://doi.org/10.1126/sciimmunol.ade5705

TY - JOUR

T1 - NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome

AU - Chen, Rui

AU - Lukianova, Elena

AU - Loeff, Ina Schim van der

AU - Spegarova, Jarmila Stremenova

AU - Willet, Joseph D.P.

AU - James, Kieran D

AU - Ryder, Edward

AU - IJspeert, Hanna

AU - Gajbhiye, Akshada

AU - Lamoliatte, Frederic

AU - Marín-Rubio, José Luis

AU - Woodbine, Lisa

AU - Lemos, Henrique

AU - Swan, David J.

AU - Pintar, Valeria

AU - Sayes, Kamal

AU - Ruiz-Morales, Elias Rafael

AU - Eastham, Simon

AU - Dixon, David

AU - Prete, Martin

AU - Prigmore, Elena

AU - Jeggo, Penny

AU - Boyes, Joan

AU - Mellor, Andrew

AU - huang, lei

AU - Burg, Mirjam van der

AU - Engelhardt, Karin Regine

AU - Stray-Pedersen, Asbjørg

AU - Erichsen, Hans Christian

AU - Gennery, Andrew

AU - Trost, Matthias

AU - anderson, graham

AU - Lorenc, Anna

AU - Trynka, Gosia

AU - Hambleton, Sophie

PY - 2024/5/24

Y1 - 2024/5/24

N2 - 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.

AB - 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.

UR - http://dx.doi.org/10.1126/sciimmunol.ade5705

U2 - 10.1126/sciimmunol.ade5705

DO - 10.1126/sciimmunol.ade5705

M3 - Article (Academic Journal)

C2 - 38787962

SN - 2470-9468

VL - 9

SP - eade5705

JO - Science Immunology

JF - Science Immunology

IS - 95

M1 - eade5705

ER -

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

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