Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients
- Author
- Evi Duthoo (UGent) , Elien Beyls (UGent) , Lynn Backers (UGent) , Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere (UGent) , Sebastian Riemann (UGent) , Bram Parton (UGent) , Likun Du, Veronique Debacker (UGent) , Marieke De Bruyne (UGent) , Levi Hoste (UGent) , Ans Baeyens (UGent) , Anne Vral (UGent) , Eva Van Braeckel (UGent) , Jens Staal (UGent) , Geert Mortier (UGent) , Tessa Kerre (UGent) , Qiang Pan-Hammarström, Claus S. Sørensen, Filomeen Haerynck (UGent) , Kathleen Claes (UGent) and Simon Tavernier (UGent)
- Organization
- Project
-
- Harnessing transcriptome and proteome wide analyses and engineered reporter assays to unravel the immunopathogenesis of 'multisystem inflammatory syndrome in children' (MIS-C).
- Elucidating the immunomodulatory role of sex hormones in asthma
- RAPID - Radiosensitivity Analysis for patients with a Primary Immunodeficiency Disease
- Abstract
- Ataxia telangiectasia and Rad3-related (ATR) kinase and its interacting protein ATRIP orchestrate the replication stress response. Homozygous splice variants in the ATRIP gene, resulting in ATRIP deficiency, were identified in two patients of independent ancestry with microcephaly, primordial dwarfism, and recurrent infections. The c.829+5G>T patient exhibited lymphopenia, poor vaccine responses, autoimmune features with hemolytic anemia, and neutropenia. Immunophenotyping revealed reduced CD16(+)/CD56(dim) NK cells and absent na & iuml;ve T cells, MAIT cells, and iNKT cells. Lymphocytic defects were characterized by TCR oligoclonality, abnormal class switch recombination, and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation under genotoxic stress. ATRIP-deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-Select(TIME) confirmed reduced cell fitness for both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP's critical role in protecting immune cells from replication stress, and offers new insights into its canonical functions.
- Keywords
- DNA-DAMAGE RESPONSE, SINGLE-STRANDED-DNA, ATAXIA-TELANGIECTASIA, GROWTH-RETARDATION, SECKEL-SYNDROME, ESSENTIAL KINASE, SHORT STATURE, GENE ATR, CELL, MUTATION
Downloads
-
(...).pdf
- full text (Published version)
- |
- UGent only
- |
- |
- 8.14 MB
Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01JPACYVGEM12294KEWQAJADTN
- MLA
- Duthoo, Evi, et al. “Replication Stress, Microcephalic Primordial Dwarfism, and Compromised Immunity in ATRIP Deficient Patients.” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 222, no. 5, 2025, doi:10.1084/jem.20241432.
- APA
- Duthoo, E., Beyls, E., Backers, L., Gudjónsson, T., Huang, P., Jonckheere, L., … Tavernier, S. (2025). Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients. JOURNAL OF EXPERIMENTAL MEDICINE, 222(5). https://doi.org/10.1084/jem.20241432
- Chicago author-date
- Duthoo, Evi, Elien Beyls, Lynn Backers, Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere, Sebastian Riemann, et al. 2025. “Replication Stress, Microcephalic Primordial Dwarfism, and Compromised Immunity in ATRIP Deficient Patients.” JOURNAL OF EXPERIMENTAL MEDICINE 222 (5). https://doi.org/10.1084/jem.20241432.
- Chicago author-date (all authors)
- Duthoo, Evi, Elien Beyls, Lynn Backers, Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere, Sebastian Riemann, Bram Parton, Likun Du, Veronique Debacker, Marieke De Bruyne, Levi Hoste, Ans Baeyens, Anne Vral, Eva Van Braeckel, Jens Staal, Geert Mortier, Tessa Kerre, Qiang Pan-Hammarström, Claus S. Sørensen, Filomeen Haerynck, Kathleen Claes, and Simon Tavernier. 2025. “Replication Stress, Microcephalic Primordial Dwarfism, and Compromised Immunity in ATRIP Deficient Patients.” JOURNAL OF EXPERIMENTAL MEDICINE 222 (5). doi:10.1084/jem.20241432.
- Vancouver
- 1.Duthoo E, Beyls E, Backers L, Gudjónsson T, Huang P, Jonckheere L, et al. Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients. JOURNAL OF EXPERIMENTAL MEDICINE. 2025;222(5).
- IEEE
- [1]E. Duthoo et al., “Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients,” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 222, no. 5, 2025.
@article{01JPACYVGEM12294KEWQAJADTN,
abstract = {{Ataxia telangiectasia and Rad3-related (ATR) kinase and its interacting protein ATRIP orchestrate the replication stress response. Homozygous splice variants in the ATRIP gene, resulting in ATRIP deficiency, were identified in two patients of independent ancestry with microcephaly, primordial dwarfism, and recurrent infections. The c.829+5G>T patient exhibited lymphopenia, poor vaccine responses, autoimmune features with hemolytic anemia, and neutropenia. Immunophenotyping revealed reduced CD16(+)/CD56(dim) NK cells and absent na & iuml;ve T cells, MAIT cells, and iNKT cells. Lymphocytic defects were characterized by TCR oligoclonality, abnormal class switch recombination, and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation under genotoxic stress. ATRIP-deficient cells inadequately regulated DNA replication, leading to chromosomal instability, compromised cell cycle control, and impaired cell viability. CRISPR-Select(TIME) confirmed reduced cell fitness for both variants. This study establishes ATRIP deficiency as a monogenic cause of microcephalic primordial dwarfism, highlights ATRIP's critical role in protecting immune cells from replication stress, and offers new insights into its canonical functions.}},
articleno = {{e20241432}},
author = {{Duthoo, Evi and Beyls, Elien and Backers, Lynn and Gudjónsson, Thorkell and Huang, Peiquan and Jonckheere, Leander and Riemann, Sebastian and Parton, Bram and Du, Likun and Debacker, Veronique and De Bruyne, Marieke and Hoste, Levi and Baeyens, Ans and Vral, Anne and Van Braeckel, Eva and Staal, Jens and Mortier, Geert and Kerre, Tessa and Pan-Hammarström, Qiang and Sørensen, Claus S. and Haerynck, Filomeen and Claes, Kathleen and Tavernier, Simon}},
issn = {{0022-1007}},
journal = {{JOURNAL OF EXPERIMENTAL MEDICINE}},
keywords = {{DNA-DAMAGE RESPONSE,SINGLE-STRANDED-DNA,ATAXIA-TELANGIECTASIA,GROWTH-RETARDATION,SECKEL-SYNDROME,ESSENTIAL KINASE,SHORT STATURE,GENE ATR,CELL,MUTATION}},
language = {{eng}},
number = {{5}},
pages = {{33}},
title = {{Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients}},
url = {{http://doi.org/10.1084/jem.20241432}},
volume = {{222}},
year = {{2025}},
}
- Altmetric
- View in Altmetric
- Web of Science
- Times cited: