Very early-onset inflammatory bowel disease (VEO-IBD), defined by the onset of IBD before 6 years of age, is often associated with more severe and extensive disease than IBD in older patients. Some VEO-IBD cases have been linked to mutations in primary immunodeficiency genes, which regulate immunity and hyperinflammatory pathways, however the underlying pathophysiological mechanisms are still poorly understood. Here we describe eight patients from four unrelated families manifesting with VEO-IBD, immunodeficiency and severe bilateral sensorineural hearing loss - each carrying either heterozygous or compound heterozygous deleterious mutations in Syntaxin-Binding Protein 3 gene (STXBP3). These mutations interfere with either intron splicing or protein stability, lead to reduced STXBP3 protein expression, which in turn, affect cytotoxic T-Lymphocyte (CTL) and epithelial cell function. STXBP3 knock-down in control CTLs significantly reduces cytotoxic activity, mimicking the patients’ CTL defects. Strikingly, forced expression of STXBP3 rescues patient CTL function. Live-cell microscopy analyses show that STXBP3 is required for recycling of RAB11A-containing endosomes to the plasma membrane. Defects in this process prevent the delivery of key effector proteins that are required for granule secretion and epithelial cell polarity. Our results identify STXBP3 as a causal gene for the development of VEO-IBD with associated immunodeficiency and hearing loss.
