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 J Ryder; Helen Griffin; Hanna IJspeert; Akshada Gajbhiye; Frederic Lamoliatte; Jose L Marin-Rubio; Lisa Woodbine; Henrique Lemos; David J Swan; Valeria Pintar; Kamal Sayes; Elias R Ruiz-Morales; Simon Eastham; David Dixon; Martin Prete; Elena Prigmore; Penny Jeggo; Joan Boyes; Andrew Mellor; Lei Huang; Mirjam van der Burg; Karin R Engelhardt; Asbjørg Stray-Pedersen; Hans Christian Erichsen; Andrew R Gennery; Matthias Trost; David J Adams; 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 J Ryder, Helen Griffin, Hanna IJspeert, Akshada Gajbhiye, Frederic Lamoliatte, Jose L Marin-Rubio, Lisa Woodbine, Henrique Lemos, David J Swan, Valeria Pintar, Kamal Sayes, Elias R Ruiz-Morales, Simon Eastham, David DixonMartin Prete, Elena Prigmore, Penny Jeggo, Joan Boyes, Andrew Mellor, Lei Huang, Mirjam van der Burg, Karin R Engelhardt, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Andrew R Gennery, Matthias Trost, David J Adams, Graham Anderson, Anna Lorenc, Gosia Trynka, Sophie Hambleton^*

^*Corresponding author for this work

Immunology and Immunotherapy

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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
Number of pages	17
Journal	Science Immunology
Volume	9
Issue number	95
DOIs	https://doi.org/10.1126/sciimmunol.ade5705
Publication status	Published - 24 May 2024

Keywords

Humans
Severe Combined Immunodeficiency/genetics
Animals
Mice
V(D)J Recombination/immunology
Male
Female
Infant
B-Lymphocytes/immunology
Homeodomain Proteins/genetics
T-Lymphocytes/immunology
Child, Preschool
Mutation, Missense

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10.1126/sciimmunol.ade5705

ChenR2024NUDCD3Accepted author manuscript, 1.07 MBLicence: Creative Commons: Attribution (CC BY)

Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production
Anderson, G. (Principal Investigator)
Medical Research Council
1/01/21 → 31/01/27
Project: Research Councils

Cite this

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

@article{7dab82aa14e1456ba279e18552dfb268,

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.",

keywords = "Humans, Severe Combined Immunodeficiency/genetics, Animals, Mice, V(D)J Recombination/immunology, Male, Female, Infant, B-Lymphocytes/immunology, Homeodomain Proteins/genetics, T-Lymphocytes/immunology, Child, Preschool, Mutation, Missense",

author = "Rui Chen and Elena Lukianova and {van der Loeff}, {Ina Schim} and Spegarova, {Jarmila Stremenova} and Willet, {Joseph D P} and James, {Kieran D} and Ryder, {Edward J} and Helen Griffin and Hanna IJspeert and Akshada Gajbhiye and Frederic Lamoliatte and Marin-Rubio, {Jose L} and Lisa Woodbine and Henrique Lemos and Swan, {David J} and Valeria Pintar and Kamal Sayes and Ruiz-Morales, {Elias R} 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 {van der Burg}, Mirjam and Engelhardt, {Karin R} and Asbj{\o}rg Stray-Pedersen and Erichsen, {Hans Christian} and Gennery, {Andrew R} and Matthias Trost and Adams, {David J} and Graham Anderson and Anna Lorenc and Gosia Trynka and Sophie Hambleton",

year = "2024",

month = may,

day = "24",

doi = "10.1126/sciimmunol.ade5705",

language = "English",

volume = "9",

journal = "Science Immunology",

issn = "2470-9468",

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

number = "95",

}

Chen, R, Lukianova, E, van der Loeff, IS, Spegarova, JS, Willet, JDP, James, KD, Ryder, EJ, Griffin, H, IJspeert, H, Gajbhiye, A, Lamoliatte, F, Marin-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, van der Burg, M, Engelhardt, KR, Stray-Pedersen, A, Erichsen, HC, Gennery, AR, Trost, M, Adams, DJ, 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. 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 - van der Loeff, Ina Schim

AU - Spegarova, Jarmila Stremenova

AU - Willet, Joseph D P

AU - James, Kieran D

AU - Ryder, Edward J

AU - Griffin, Helen

AU - IJspeert, Hanna

AU - Gajbhiye, Akshada

AU - Lamoliatte, Frederic

AU - Marin-Rubio, Jose L

AU - Woodbine, Lisa

AU - Lemos, Henrique

AU - Swan, David J

AU - Pintar, Valeria

AU - Sayes, Kamal

AU - Ruiz-Morales, Elias R

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 - van der Burg, Mirjam

AU - Engelhardt, Karin R

AU - Stray-Pedersen, Asbjørg

AU - Erichsen, Hans Christian

AU - Gennery, Andrew R

AU - Trost, Matthias

AU - Adams, David J

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.

KW - Humans

KW - Severe Combined Immunodeficiency/genetics

KW - Animals

KW - Mice

KW - V(D)J Recombination/immunology

KW - Male

KW - Female

KW - Infant

KW - B-Lymphocytes/immunology

KW - Homeodomain Proteins/genetics

KW - T-Lymphocytes/immunology

KW - Child, Preschool

KW - Mutation, Missense

U2 - 10.1126/sciimmunol.ade5705

DO - 10.1126/sciimmunol.ade5705

M3 - Article

C2 - 38787962

SN - 2470-9468

VL - 9

JO - Science Immunology

JF - Science Immunology

IS - 95

M1 - eade5705

ER -

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

Abstract

Keywords

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Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production

Cite this