The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Dhingani, Neel; Guo, Conghui; Pan, Jie; Li, Qi; Warner, Neil; Jardine, Sasha; Leung, Gabriella; Kotlarz, Daniel; Gonzaga‐Jauregui, Claudia; Klein, Christoph; Snapper, Scott B.; Navas-López, Víctor Manuel; Muise, Aleixo M.

doi:10.1038/s41598-020-73482-6

Cited by 7 publications

(7 citation statements)

References 65 publications

(71 reference statements)

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“…Functional studies identified that TTC7A binds to phosphatidylinositol 4‐Kinase and that loss of TTC7A in intestinal cell lines results in reduced cellular adhesion and increased apoptosis 28 . TTC7A interacts with ubiquitin protein ligase E3 component N‐regognin5 (UBR5) and recently a patient with a UBR5 mutation with VEOIBD has been identified 29 . A high‐throughput screen of compounds identified a medication, leflunomide, which increased viability in TTC7A deficient cells and may provide hope of a therapeutic intervention in this severe disease.…”

Section: Known Monogenic Causes Of Veoibdmentioning

confidence: 99%

Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity

Hall,

de Zoeten

2023

Immunological Reviews

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SummaryInflammatory bowel diseases (IBD) are multifactorial diseases which are caused by the combination of genetic predisposition, exposure factors (environmental and dietary), immune status, and dysbiosis. IBD is a disease which presents at any age, ranging from newborns to the elderly. The youngest of the pediatric IBD population have a more unique presentation and clinical course and may have a different etiology. Very early onset IBD (VEOIBD) patients, designated as those diagnosed prior the age of 6, have distinct features which are more frequent in this patient population including increased incidence of monogenetic causes for IBD (0%–33% depending on the study). This proportion is increased in the youngest subsets, which is diagnosed prior to the age of 2. To date, there are approximately 80 monogenic causes of VEOIBD that have been identified and published. Many of these monogenic causes are inborn errors of immunity yet the majority of VEOIBD patients do not have an identifiable genetic cause for their disease. In this review, we will focus on the clinical presentation, evaluation, and monogenic categories which have been associated with VEOIBD including (1) Epithelial cell defects (2) Adaptive immune defects, (3) Innate Immune/Bacterial Clearance and Recognition defects, and (4) Hyperinflammatory and autoinflammatory disorders. We will highlight differential diagnosis of VEOIBD presentations, as well as evaluation and treatment, which will be helpful for those who study and care for VEOIBD patients outside of the pediatric gastroenterology field. This is a fast‐moving field of research which has grown significantly based on knowledge that we gain from our patients. These scientific findings have identified novel mucosal biology pathways and will continue to inform our understanding of gastrointestinal biology.

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Section: Known Monogenic Causes Of Veoibdmentioning

confidence: 99%

Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity

Hall,

de Zoeten

2023

Immunological Reviews

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“…For the known monogenic IBD-associated genes, we reviewed current definitive guidelines 4,16 and recent publications. 17,18 The Closest Disease-causing Gene (CDG) list was created from the 99 known monogenic IBD genes, using the online Human Gene Mutation Database CDG server (http://pec630.rockefeller. edu:8080/CDG-OMIM/).…”

Section: Variant Annotation and Feature Selectionmentioning

confidence: 99%

A Machine Learning Approach to Identifying Causal Monogenic Variants in Inflammatory Bowel Disease

Mulder

Khalouei

Warner

et al. 2022

Gastro Hep Advances

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BACKGROUND AND AIMS: Diagnosis of monogenic disease is increasingly important for patient care and personalizing therapy. However, the current process is nonstandardized, expensive, and time consuming. There is currently no accepted strategy to help identify disease-causing variants in monogenic inflammatory bowel disease (IBD). The aim of the study is to develop a prioritization strategy for monogenic IBD variant discovery through detailed analysis of a whole-exome sequencing (WES) data set. METHODS: All consenting pediatric patients with IBD presenting to our tertiary care hospital during the study period were enrolled and underwent WES (n ¼ 1005). Available family members also underwent WES. Variants were analyzed en masse using the GEMINI framework and were further annotated using data from dbNSFP, Combined Annotation Dependent Depletion, and gno-mAD. Known disease-causing variants (n ¼ 36) were used as positive controls. Machine learning algorithms were optimized and then compared to assist with identifying monogenic IBD case characteristics. RESULTS: Initial gene-level analysis identified 11 genes not previously linked to IBD that could potentially harbor IBD-causing variants. Machine learning algorithms identified 4 primary variant characteristics (Combined Annotation Dependent Depletion score, dbNSFP score, relationship with a known immunodeficiency gene, and alternate allele frequency), and optimal threshold values for each were determined to assist with identifying monogenic IBD variants. Based on these characteristics, an automated variant prioritization pipeline was then created that filters and prioritizes variants from >100,000 variants per patient down to a mean of 15. This pipeline is available online for all to use. CONCLUSION: Leveraging a large WES data set, we demonstrate a statistically rigorous strategy for prioritization of variants for monogenic IBD diagnosis.

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“…For example, HERC2 was found to be a susceptibility gene for UC ( 121 , 188 ). In addition, UBR5, which is another HECTE3 ubiquitin ligase, was reported to interact with tetratricopeptide repeat domain 7A (TTC7A) and be associated with VEOIBD ( 189 ). Meanwhile, mutations in TTC7A are a pivotal pathogenic event in VEOIBD ( 190 ).…”

Section: Ub E3 Ligases and Ibdmentioning

confidence: 99%

The Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?

et al. 2021

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Inflammatory bowel disease (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), exhibits a complex multifactorial pathogenesis involving genetic susceptibility, imbalance of gut microbiota, mucosal immune disorder and environmental factors. Recent studies reported associations between ubiquitination and deubiquitination and the occurrence and development of inflammatory bowel disease. Ubiquitination modification, one of the most important types of post-translational modifications, is a multi-step enzymatic process involved in the regulation of various physiological processes of cells, including cell cycle progression, cell differentiation, apoptosis, and innate and adaptive immune responses. Alterations in ubiquitination and deubiquitination can lead to various diseases, including IBD. Here, we review the role of E3 ubiquitin ligases and deubiquitinases (DUBs) and their mediated ubiquitination and deubiquitination modifications in the pathogenesis of IBD. We highlight the importance of this type of posttranslational modification in the development of inflammation, and provide guidance for the future development of targeted therapeutics in IBD.

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The E3 ubiquitin ligase UBR5 interacts with TTC7A and may be associated with very early onset inflammatory bowel disease

Cited by 7 publications

References 65 publications

Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity

Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity

A Machine Learning Approach to Identifying Causal Monogenic Variants in Inflammatory Bowel Disease

The Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?

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