Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients

Evi Duthoo^#^{1

2

3}, Elien Beyls^#^{1

2

3}, Lynn Backers^#^{1

4

5}, Thorkell Gudjónsson⁶, Peiquan Huang⁶, Leander Jonckheere^{7

8}, Sebastian Riemann^{8

9}, Bram Parton^{4

5}, Likun Du¹⁰, Veronique Debacker^{1

2}, Marieke De Bruyne^{4

5}, Levi Hoste^{1

11}, Ans Baeyens¹², Anne Vral¹², Eva Van Braeckel^{7

8}, Jens Staal^{13

14}, Geert Mortier¹⁵, Tessa Kerre^{2

16}, Qiang Pan-Hammarström¹⁰, Claus S Sørensen⁶, Filomeen Haerynck^#^{1

2

17}, Kathleen B M Claes^#^{4

5}, Simon J Tavernier^#^{1

2

4

13

14}

Affiliations

¹ Primary Immunodeficiency Research Lab (PIRL), Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
² Center for Primary Immunodeficiency, Jeffrey Modell Diagnosis and Research Center, ERN-RITA Reference Center, Ghent University Hospital , Ghent, Belgium.
³ Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
⁴ Center for Medical Genetics, Ghent University Hospital , Ghent, Belgium.
⁵ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
⁶ Biotech Research and Innovation Centre (BRIC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Respiratory Infection and Defense Lab (RIDL), Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
⁸ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
⁹ Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
¹⁰ Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
¹¹ Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
¹² Radiobiology Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
¹³ Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
¹⁴ Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
¹⁵ Center for Human Genetics, University Hospitals Leuven , Leuven, Belgium.
¹⁶ Department of Hematology, Ghent University Hospital, Ghent, Belgium.
¹⁷ Department of Pediatric Respiratory and Infectious Medicine, Ghent University Hospital, Ghent, Belgium.

^# Contributed equally.

PMID: 40029331
PMCID: PMC11874998 (available on 2026-03-03)
DOI: 10.1084/jem.20241432

Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients

Evi Duthoo et al. J Exp Med. 2025.

. 2025 May 5;222(5):e20241432.

doi: 10.1084/jem.20241432. Epub 2025 Mar 3.

Authors

Affiliations

¹ Primary Immunodeficiency Research Lab (PIRL), Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
² Center for Primary Immunodeficiency, Jeffrey Modell Diagnosis and Research Center, ERN-RITA Reference Center, Ghent University Hospital , Ghent, Belgium.
³ Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
⁴ Center for Medical Genetics, Ghent University Hospital , Ghent, Belgium.
⁵ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
⁶ Biotech Research and Innovation Centre (BRIC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Respiratory Infection and Defense Lab (RIDL), Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
⁸ Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
⁹ Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
¹⁰ Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
¹¹ Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
¹² Radiobiology Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
¹³ Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
¹⁴ Unit of Molecular Signal Transduction in Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
¹⁵ Center for Human Genetics, University Hospitals Leuven , Leuven, Belgium.
¹⁶ Department of Hematology, Ghent University Hospital, Ghent, Belgium.
¹⁷ Department of Pediatric Respiratory and Infectious Medicine, Ghent University Hospital, Ghent, Belgium.

^# Contributed equally.

PMID: 40029331
PMCID: PMC11874998 (available on 2026-03-03)
DOI: 10.1084/jem.20241432

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+/CD56dim NK cells and absent naïve 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-SelectTIME 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.

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Conflict of interest statement

Disclosures: S. Riemann reported grants from Ghent University (predoctoral mandate BOF23/DOC/013), non-financial support from AstraZeneca, and non-financial support from GSK outside the submitted work. L. Jonckheere reported a grant from the Research Foundation—Flanders (FWO) (predoctoral mandate 11J2525N). C.S. Sørensen reported a patent to the European Patent Office, application no. 21816113.1 on CRISPR-Select pending. No other disclosures were reported.

References

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Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients

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Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients

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