HUMAN GENETIC VARIANTS IN ESSENTIAL SPLICING FACTORS AND THEIR IMPACT ON IMMUNE PATHOLOGY

Pre-mRNA splicing is critical for proper gene expression, and its dysregulation has been implicated in many human diseases including neurodegenerative disorders, cancers and autoimmune diseases. Splicing is a multi-step process executed by the spliceosome, which is composed of five small nuclear ribonucleoproteins (snRNPs) and hundreds of proteins that are generally referred to as splicing factors (SFs). Here we present two unique cases in which genetic variations in two essential SFs, DExD-box polypeptide 39B (DDX39B) and U2 small nuclear RNA auxiliary factor 1 (U2AF1), contribute to altered splicing of Forkhead box P3 (FOXP3) – an immunoregulatory gene critical for regulatory T (Treg) cell function and homeostasis. Mutations in FOXP3 cause immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, and aberrant expression of FOXP3 has been associated with other diseases such as multiple sclerosis (MS) and non-small cell lung cancer (NSCLC). We previously described a single nucleotide polymorphism (SNP) in DDX39B, rs2523506, which is associated with increased risk of MS. The population homozygous for the risk allele had ~50% less DDX39B protein expression. Furthermore, we demonstrated that DDX39B expression is critical for proper splicing, expression and function of FOXP3. Here we describe the mechanism underlying the exquisite dependence of FOXP3 introns on DDX39B and the potential impact of rs2523506 in DDX39B on FOXP3 expression and autoimmunity. Additionally, we highlight splicing alterations in a patient with a complex immune phenotype and a de novo in-frame deletion in U2AF1. Moreover, we discuss the potential implications of these splicing alterations in the disease pathogenesis of the patient. These two examples of genetic variations in SFs showcase the importance of splicing and how its dysregulation can contribute to immune pathology.