Abstract
Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. A number of monogenic disorders are associated with VEOIBD including tetratricopeptide repeat domain 7A (TTC7A) deficiency. TTC7A-deficiency is characterized by apoptotic colitis in milder cases with severe intestinal atresia and immunodeficiency in cases with complete loss of protein. We used whole exome sequencing in a VEOIBD patient presenting with colitis characterized by colonic apoptosis and no identified known VEOIBD variants, to identify compound heterozygous deleterious variants in the Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) gene. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis.
Highlights
Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age
PI4KIIIα is involved in the production of phosphatidylinositol 4-phosphate (PI4P) at the plasma membrane (PM)[26,27] with the help of Tetratricopeptide Repeat Domain 7A (TTC7A) and FAM126A which scaffold PI4KIIIα from endoplasmic reticulum to PM where the complex interacts with EFR3A/B28,29
We have recently demonstrated that 3% of pediatric IBD patients have monogenic forms of IBD12
Summary
Very early onset inflammatory bowel disease (VEOIBD) denotes children with onset of IBD before six years of age. Functional studies demonstrated that UBR5 co-immunoprecipitates with the TTC7A and the UBR5 variants had reduced interaction between UBR5 and TTC7A. Together this implicates UBR5 in regulating TTC7A signaling in VEOIBD patients with apoptotic colitis. Recent studies have demonstrated that approximately 3% of Pediatric IBD patients have a monogenic cause for their disease and younger age at diagnosis is a risk factor[12]. VEOIBD patients with TTC7A variants have apoptotic enterocolitis and functional studies show loss of interaction with Phosphatidylinositol 4-kinase Type III Alpha (PI4KIIIα) to be the causative factor[1]. We identified Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) as a Tetratricopeptide Repeat Domain 7A (TTC7A) interacting protein using tandem mass spectrometry[1]. Functional studies demonstrate that UBR5 co-immunoprecipitates (co-IP) with TTC7A implicating UBR5 in the TTC7A-PI4KIIIα complex signalling
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