Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Common variable immunodeficiency disorders (CVID) present with low immunoglobulins and susceptibility to bacterial infections.
• CVID patients may exhibit diverse clinical courses, including inflammatory, autoimmune, and malignant complications.
• The role of deficient DNA repair mechanisms in CVID pathogenesis remains under investigation.

Purpose of the Study:

• To investigate the hypothesis that impaired DNA repair mechanisms contribute to antibody deficiency and complex disease phenotypes in CVID.
• To identify genetic variants and altered gene expression signatures associated with DNA repair pathways in CVID patients.

Main Methods:

• Germline variants were identified using targeted sequencing of 252 DNA repair genes in 38 CVID patients.
• Gene expression was analyzed using NanoString nCounter PlexSet assay in 20 CVID patients and 7 controls.
• DNA damage and apoptosis were assessed by flow cytometry in 34 CVID patients and 11 controls.

Main Results:

• Targeted sequencing revealed enrichment of rare genetic variants in DNA repair pathways, including novel pathogenic variants.
• An altered gene expression signature distinguished CVID patients from controls and complex CVID from infection-only phenotypes.
• Flow cytometry showed downregulated ATM in a subset of CVID patients, impairing DNA repair and promoting apoptosis.

Conclusions:

• Germline genetics and altered gene expression contribute to increased DNA damage sensitivity and reduced DNA repair capacity in a subset of CVID patients.
• These findings suggest a link between DNA repair defects and the complex clinical manifestations of CVID.
• Further research into DNA repair pathways may offer novel therapeutic targets for CVID management.