Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation

Abstract

Background and Aims Very early onset inflammatory bowel disease (VEOIBD) is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic etiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. Methods Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss, and, in the majority, recurrent infections. Genetic etiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on PBMCs and functional studies with epithelial cell lines were employed. Results In each of the 10 patients, we identified damaging heterozygous or biallelic variants in Syntaxin-Binding Protein 3 gene (STXBP3), a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and led to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Conclusion Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

“…Damaging mutations in STXBP3 , a related gene also important in regulating intracellular vesicular trafficking, results in life-threatening infantile-onset IBD of both large and small intestine, usually associated with hearing loss ( 36 ). STXBP3 is expressed in epithelial and immune cells and is required for IEC polarization ( 36 ).…”

“…Damaging mutations in STXBP3 , a related gene also important in regulating intracellular vesicular trafficking, results in life-threatening infantile-onset IBD of both large and small intestine, usually associated with hearing loss ( 36 ). STXBP3 is expressed in epithelial and immune cells and is required for IEC polarization ( 36 ). Intestinal disease is histologically characterized by lymphoplasmacytic inflammation, neutrophilic crypt abscesses, villous atrophy, eosinophilia, apoptosis, and crypt destruction ( 36 ).…”

“…STXBP3 is expressed in epithelial and immune cells and is required for IEC polarization ( 36 ). Intestinal disease is histologically characterized by lymphoplasmacytic inflammation, neutrophilic crypt abscesses, villous atrophy, eosinophilia, apoptosis, and crypt destruction ( 36 ). Colitis is refractory to immune suppression ( 36 ).…”

“…Intestinal disease is histologically characterized by lymphoplasmacytic inflammation, neutrophilic crypt abscesses, villous atrophy, eosinophilia, apoptosis, and crypt destruction ( 36 ). Colitis is refractory to immune suppression ( 36 ). One patient described exhibited remission of colitis following bone marrow transplant (BMT), while colectomies were curative in four ( 36 ).…”

“…Colitis is refractory to immune suppression ( 36 ). One patient described exhibited remission of colitis following bone marrow transplant (BMT), while colectomies were curative in four ( 36 ).…”