Combined Immunodeficiency Caused by a Novel De Novo Gain-of-Function RAC2 Mutation.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Ras-related C3 botulinum toxin substrate 2 (RAC2) is a GTPase crucial for hematopoietic cell function, acting as a molecular switch.
• RAC2's GTP-binding/hydrolysis cycle regulates cell behavior, and its mutations are linked to various primary immunodeficiencies.

Observation:

• An 11-year-old girl with combined immunodeficiency presented with recurrent respiratory infections and bronchiectasis.
• Immunological tests showed low T-cell receptor excision circle/K-deleting recombination excision circles, lymphopenia, and low immunoglobulin G.

Findings:

• A novel heterozygous RAC2 mutation (c.86C>G, p.P29R) in the Switch I domain was identified.
• This gain-of-function mutation enhanced reactive oxygen species and F-actin production, increased RAC2 expression in neutrophils, and dysregulated T lymphocyte function.
• The mutation also caused accelerated apoptosis, impaired actin and RAC2 polarization in immune cells.

Implications:

• This study identifies a novel RAC2 gain-of-function mutation contributing to combined immunodeficiency.
• The findings highlight the role of altered RAC2 expression and function in abnormal apoptosis and cell polarization.
• This expands the understanding of RAC2-related immunodeficiencies and their molecular mechanisms.