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

• DOI: 10.1084/jem.20241432
• Publication Date: 2025-03-03T14:39:31Z
• Authors: Evi Duthoo; 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-Hammars...; Claus S. Sørensen; Filomeen Haerynck; Kathleen B.M. Claes; Simon J. Tavernier

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.