Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Cell Biology

Background:

• The MRE11-RAD50-NBN (MRN) complex is crucial for DNA double-strand break repair.
• Pathogenic variants in NBN and MRE11 cause Nijmegen breakage syndrome (NBS) and ataxia telangiectasia-like disorder.
• The clinical impact of RAD50 variants remains poorly understood.

Purpose of the Study:

• To characterize a patient with RAD50 deficiency presenting as Nijmegen breakage syndrome-like disorder (NBSLD).
• To investigate the cellular and molecular consequences of novel RAD50 variants.
• To define the role of RAD50 in bone marrow failure and immunodeficiency.

Main Methods:

• Whole-exome sequencing to identify candidate genes.
• Analysis of patient-derived fibroblasts.
• Immunoblotting, radiation sensitivity assays, and lentiviral complementation experiments.

Main Results:

• Compound heterozygous RAD50 variants (p.Arg83His and p.Glu485Ter) were identified.
• DNA damage-induced ATM kinase activation was impaired but restored by wild-type RAD50.
• Specific RAD50 variants affected mitotic stability and complex formation.

Conclusions:

• RAD50 plays a critical role in human bone marrow and immune cells.
• RAD50 deficiency/NBSLD is an inborn error of immunity characterized by bone marrow failure and B-cell immunodeficiency.