ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency
- 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 Storgaard Sørensen, Filomeen Haerynck (UGent) , Kathleen Claes (UGent) and Simon Tavernier (UGent)
- Organization
- Abstract
- ATR (Ataxia Telangiectasia and Rad3-related) kinase and its interacting protein ATRIP orchestrate the replication stress response. Two patients of independent ancestry with microcephaly, primordial dwarfism, and recurring infections were found to be homozygous for splice donor site variants of ATRIP exon 5, resulting in ATRIP deficiency. The c.829+5G>T patient exhibited autoimmune hemolytic anemia, lymphopenia, poor vaccine response, and intermittent neutropenia. Immunophenotyping revealed reduced CD16+ NK cells and absent naïve T cells, mucosal-associated invariant T cells (MAITs), and invariant natural killer T cells (iNKTs). Lymphocytic defects were characterized by T cell receptor (TCR) oligoclonality, abnormal class switch recombination (CSR), and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation upon genotoxic stress. Consequently, 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 induced by 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 brings a renewed perspective to the canonical functions of ATRIP.
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Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01J46SQYRP0YNXKB6XRCF3VBDH
- MLA
- Duthoo, Evi, et al. “ATRIP Deficiency Impairs the Replication Stress Response and Manifests as Microcephalic Primordial Dwarfism and Immunodeficiency.” MEDRXIV, 2024, doi:10.1101/2024.07.22.24310550.
- APA
- Duthoo, E., Beyls, E., Backers, L., Gudjónsson, T., Huang, P., Jonckheere, L., … Tavernier, S. (2024). ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency. https://doi.org/10.1101/2024.07.22.24310550
- Chicago author-date
- Duthoo, Evi, Elien Beyls, Lynn Backers, Thorkell Gudjónsson, Peiquan Huang, Leander Jonckheere, Sebastian Riemann, et al. 2024. “ATRIP Deficiency Impairs the Replication Stress Response and Manifests as Microcephalic Primordial Dwarfism and Immunodeficiency.” MEDRXIV. https://doi.org/10.1101/2024.07.22.24310550.
- 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 Storgaard Sørensen, Filomeen Haerynck, Kathleen Claes, and Simon Tavernier. 2024. “ATRIP Deficiency Impairs the Replication Stress Response and Manifests as Microcephalic Primordial Dwarfism and Immunodeficiency.” MEDRXIV. doi:10.1101/2024.07.22.24310550.
- Vancouver
- 1.Duthoo E, Beyls E, Backers L, Gudjónsson T, Huang P, Jonckheere L, et al. ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency. MEDRXIV. 2024.
- IEEE
- [1]E. Duthoo et al., “ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency,” MEDRXIV. 2024.
@misc{01J46SQYRP0YNXKB6XRCF3VBDH,
abstract = {{ATR (Ataxia Telangiectasia and Rad3-related) kinase and its interacting protein ATRIP orchestrate the replication stress response. Two patients of independent ancestry with microcephaly, primordial dwarfism, and recurring infections were found to be homozygous for splice donor site variants of ATRIP exon 5, resulting in ATRIP deficiency. The c.829+5G>T patient exhibited autoimmune hemolytic anemia, lymphopenia, poor vaccine response, and intermittent neutropenia. Immunophenotyping revealed reduced CD16+ NK cells and absent naïve T cells, mucosal-associated invariant T cells (MAITs), and invariant natural killer T cells (iNKTs). Lymphocytic defects were characterized by T cell receptor (TCR) oligoclonality, abnormal class switch recombination (CSR), and impaired T cell proliferation. ATRIP deficiency resulted in low-grade ATR activation but impaired CHK1 phosphorylation upon genotoxic stress. Consequently, 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 induced by 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 brings a renewed perspective to the canonical functions of ATRIP.}},
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 Storgaard and Haerynck, Filomeen and Claes, Kathleen and Tavernier, Simon}},
language = {{eng}},
pages = {{41}},
series = {{MEDRXIV}},
title = {{ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency}},
url = {{http://doi.org/10.1101/2024.07.22.24310550}},
year = {{2024}},
}
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