INTRODUCTION
One of the most common primary immunodeficiencies (PIDs) in children is Common Variable Immunodeficiency (CVID), which is a polygenic and heterogenous disorder characterized by recurrent infections, hypogammaglobulinemia (markedly reduced immunoglobulin (Ig)G serum concentration in combination with low levels of IgA and/or IgM), autoimmunity, poor antibody response to immunizations, and absence of any other defined immunodeficient state, which makes it a diagnosis of exclusion 1-4. Only 5-25% of individuals with CVID have an affected relative, with most of them showing an autosomal dominant (AD) pattern of inheritance 5. Biallelic mutations in several genes involved in B cell stimulation have been identified and shown to be associated with autosomal recessive (AR) hypogammaglobulinemia (CD19 6, MS4A17, CD81 8, CR29, and TNFRSF13C 10). In 2012, Lopez-Herrera et al. discovered mutations in the LRBA gene associated with the clinical presentation of CVID for the first time, which is known as LPS-responsive beige-like anchor protein (LRBA) deficiency since 1. According to the International Union of Immunological Societies, LRBA deficiency is classified as a disease of immune dysregulation due to regulatory T (Treg)-cell defects since 2018 11.
LRBA is a cytosolic protein in the BEACH-WD40 protein family, which is expressed in several cell types and tissues 1,12,13. LRBA participates in multiple cellular processes including cytoskeleton assembly, signal transduction, vesicular trafficking, transcriptional regulation, chromatin dynamics, and apoptosis, and has a role in maintaining intracellular stores of CTLA4 (cytotoxic T-lymphocyte-associated protein 4) in T-cells 12,14. However, still little is known about the definitive role of LRBA in cellular function and human biology, which remains to be clarified1,12,13.
Lopez-Herrera et al. managed to find four distinct homozygous mutations in the LRBA gene in five symptomatic individuals clinically diagnosed with CVID 1. Since then, several novel mutations in the LRBA gene have been identified and shown in many case reports of PID as well as in other disorders without hypogammaglobulinemia 15-22. Here, we report a novel mutation in LRBA in a patient with childhood-onset immunodeficiency presenting with CVID-like symptoms.