Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease

Paračková, Zuzana; Milota, Tomáš; Vrabcová, Petra; Smetanová, Jitka; Svatoň, Michael; Freiberger, Tomáš; Kanderová, Veronika; Šedivá, Anna

doi:10.1038/s41419-020-2652-4

Cited by 18 publications

(12 citation statements)

References 48 publications

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“… 1 Loss-of-function variants within these genes are associated with severe monogenic forms of Crohn’s-like IBD ( XIAP , CARD9 ), or increased risk of “classical” Crohn’s disease ( TAB2 ). Several studies have described the function of these genes in downstream NFKB signaling, including variants in XIAP 30 and CARD9 31 leading to reduced NFKB production. While the mechanism by which these genes leads to disease may not have the evidence base seen with NOD2 , it appears that a hypoinflammatory response is implicated, potentially alongside activation of additional aberrant pathways.…”

Section: Discussionmentioning

confidence: 99%

Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease

Ashton

Boukas

Stafford

et al. 2022

Inflammatory Bowel Diseases

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Background Inflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn’s disease pathogenesis, with deleterious variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription. Methods Treatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a “complex” score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription. Results Thirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (β = -0.702, P = 4.3 × 10-5) and increased NFKBIA (β = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (β = 0.8, P = 3.1475 × 10-8) and TXN (β = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (β = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (β = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients. Conclusions Data integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.

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Section: Discussionmentioning

confidence: 99%

Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease

Ashton

Boukas

Stafford

et al. 2022

Inflammatory Bowel Diseases

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“…Over half of the cohort displayed signs of impaired EBV response, consistent with previously reported data ( 8 , 9 ). Nevertheless, the infection had rather mild features, unlike the often catastrophic EBV-driven lymphoproliferative consequences in other inborn errors of immunity, such as in X-linked lymphoproliferative syndrome (XLP) or interleukin-2-inducible T-cell kinase (ITK) deficiency ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Natural Course of Activated Phosphoinositide 3-Kinase Delta Syndrome in Childhood and Adolescence

et al. 2021

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Activated phosphoinositide 3-kinase delta syndrome (APDS), caused by mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits, is a primary immunodeficiency affecting both humoral and cellular immunity, which shares some phenotypic similarities with hyper-IgM syndromes and common variable immunodeficiency (CVID). Since its first description in 2013, over 200 patients have been reported worldwide. Unsurprisingly, many of the newly diagnosed patients were recruited later in life from previously long-standing unclassified immunodeficiencies and the early course of the disease is, therefore, often less well-described. In this study, we report clinical and laboratory features of eight patients followed for APDS, with particular focus on early warning signs, longitudinal development of their symptoms, individual variations, and response to therapy. The main clinical features shared by our patients included recurrent bacterial and viral respiratory tract infections, gastrointestinal disease, non-malignant lymphoproliferation, autoimmune thyroiditis, and susceptibility to EBV. All patients tolerated vaccination with both attenuated live and subunit vaccines with no adverse effects, although some failed to mount adequate antibody response. Laboratory findings were characterized by dysgammaglobulinaemia, elevated serum IgM, block in B-cell maturation with high transitional B cells, and low naïve T cells with CD8 T-cell activation. All patients benefited from immunoglobulin replacement therapy, whereas immunosuppression with mTOR pathway inhibitors was only partially successful. Therapy with specific PI3K inhibitor leniolisib was beneficial in all patients in the clinical trial. These vignettes, summary data, and particular tell-tale signs should serve to facilitate early recognition, referral, and initiation of outcome-improving therapy.

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“…A study was performed on 12 patients with the X‐linked lymphoproliferative disease (XLP) a gene mutation encoding and leading to a BIRC4/XIAP deficiency 171 . Moreover, primary immunodeficiencies can be caused by XIAP deficiency due to the deletion of the BIRC4 gene 172 …”

Section: Mutations In the Caspase‐dependant Apoptosis Pathways That L...mentioning

confidence: 99%

Review of cancer cell resistance mechanisms to apoptosis and actual targeted therapies

Kulbay

Paimboeuf

Ozdemir

et al. 2021

J of Cellular Biochemistry

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The apoptosis pathway is a programmed cell death mechanism that is crucial for cellular and tissue homeostasis and organ development. There are three major caspase‐dependent pathways of apoptosis that ultimately lead to DNA fragmentation. Cancerous cells are known to highly regulate the apoptotic pathway and its role in cancer hallmark acquisition has been discussed over the past decades. Numerous mutations in cancer cell types have been reported to be implicated in chemoresistance and treatment outcome. In this review, we summarize the mutations of the caspase‐dependant apoptotic pathways that are the source of cancer development and the targeted therapies currently available or in trial.

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Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn’s disease

Cited by 18 publications

References 48 publications

Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease

Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease

Natural Course of Activated Phosphoinositide 3-Kinase Delta Syndrome in Childhood and Adolescence

Review of cancer cell resistance mechanisms to apoptosis and actual targeted therapies

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