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

Cell Death & Disease
Zuzana ParackovaAnna Sediva

Abstract

X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the ...Continue Reading

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Citations

Aug 6, 2021·Frontiers in Pediatrics·Marketa BloomfieldAnna Sediva
Jul 12, 2021·The Journal of Allergy and Clinical Immunology. in Practice·Shintaro OnoHirokazu Kanegane
Aug 5, 2021·Journal of Crohn's & Colitis·Roger FeakinsMonika Tripathi
Nov 19, 2021·Journal of Cellular Biochemistry·Merve KulbayJacques Bernier

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Methods Mentioned

BETA
biopsy
PMA
flow cytometry

Software Mentioned

SAMtools
SnpEff
BWA
VarScan
FLICA

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis