ATRIP deficiency impairs the replication stress response and manifests as microcephalic primordial dwarfism and immunodeficiency.
medrxiv(2024)
摘要
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.
### Competing Interest Statement
The authors have declared no competing interest.
### Funding Statement
This work was funded by Research Foundation Flanders (FWO) (FWOTBM2018000102) and VIB Grand Challenge. Simon Tavernier is a beneficiary of a senior postdoctoral FWO grant (1236923N). Sebastian Riemann is funded by Ghent University (BOF23/DOC/013). Centre for Primary Immune deficiency Ghent (CPIG) is recognized as Jeffrey Modell Diagnostic and Research center and funded by JMF foundation.
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethical approval for this study was granted by the ethics committee of Ghent University Hospital in Belgium.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
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Code for scRNA-seq data analysis will be made available on GitHub upon publication. The plasmids will be made available via GeneCorner upon publication (https://bccm.belspo.be/genecorner). The ATRIP variant will be submitted to ClinVar and the Leiden Open Variation Database (LOVD) upon publication. Correspondence and requests for materials should be addressed to corresponding authors: Filomeen Haerynck and Kathleen Claes.
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