Summary of Findings:

The study expands the understanding of the clinical spectrum and molecular basis of immune disorders associated with RAC2 mutations. A cohort of 54 patients from 37 families was analyzed, revealing three distinct clinical presentations: neonatal severe combined immunodeficiency (SCID), infantile disease resembling leukocyte adhesion deficiency (LAD), and combined immune deficiency (CID) manifesting later in life. The type of RAC2 mutation correlated with the disease phenotype:

• Constitutively-active mutations led to neonatal SCID.
• Dominant-negative mutations resulted in LAD-like disease.
• Dominant-activating mutations were associated with CID.

Patients commonly exhibited T- and B-lymphopenia, low immunoglobulin levels, neutropenia, and defects in neutrophil function. Respiratory and viral infections were prevalent among the 42 CID patients with detailed clinical data. The study identified 23 RAC2 mutations, including 15 novel variants. Functional assays using heterologous expression systems revealed that all tested RAC2 mutant proteins had abnormal functions, affecting superoxide production, PAK1 binding, AKT activation, and protein stability. Notably, mutations that impaired superoxide formation were linked to bacterial infections.

Importance: This research clarifies the relationship between specific RAC2 mutations and the severity of immune dysfunction, ranging from severe immunodeficiency to milder combined deficiencies. It underscores the complexity of RAC2’s role in immune cell function and the necessity of multiple assays to determine the functional impact of mutations.

Contribution to Literature: The study contributes to the literature by providing a comprehensive analysis of RAC2 mutations and their clinical consequences, including the identification of novel variants and their functional characterization, thereby enhancing the understanding of RAC2-related immune disorders.