Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants

Takagi, Masatoshi; Hoshino, Akihiro; Bousset, Kristine; Röddecke, Jule; Martin, Hanna Luisa; Folcut, Iulia; Tomomasa, Dan; Yang, Xi; Kobayashi, Junya; Sakata, Naoki; Yoshida, Kenichi; Miyano, Satoru; Ogawa, Seishi; Kojima, Seiji; Morio, Tomohiro; Dörk, Thilo; Kanegane, Hirokazu

doi:10.1007/s10875-023-01591-8

Cited by 2 publications

References 27 publications

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Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder

Hartlerode,

Mostafa,

Orban

et al. 2024

Human Molecular Genetics

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The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.

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Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder

Hartlerode,

Mostafa,

Orban

et al. 2024

Human Molecular Genetics

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Investigating chromosomal radiosensitivity in inborn errors of immunity: insights from DNA repair disorders and beyond

Beyls,

Duthoo,

Backers

et al. 2024

Preprint

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Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially result in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as the single influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with radiosensitivity.

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Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants

Cited by 2 publications

References 27 publications

Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder

Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder

Investigating chromosomal radiosensitivity in inborn errors of immunity: insights from DNA repair disorders and beyond

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