Abstract
Purpose
X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations.
Methods
Clinical data and laboratory findings including flow cytometric analysis of XIAP protein expression and sequencing of the BIRC4 gene. NOD2 signaling was investigated by determination of TNFα production in monocytes upon L18-MDP stimulation in vitro.
Results
The BIRC4 nonsense mutation p.P225SfsX226 was identified as the genetic cause of XIAP deficiency in our family. Surprisingly, clinical symptoms were not restricted to male patients, but also occurred in several female carriers. The most severely affected carrier demonstrated random X-inactivation, leading to a significant expression of mutated XIAP protein in monocytes, and consequently to impaired NOD2 responses in vitro.
Conclusion
Our report provides further evidence that clinical symptoms of XIAP deficiency are not restricted to male patients. Random X-inactivation may be associated with EN and mild IBD also in female carriers of BIRC4 mutations. Analysis of the X-inactivation pattern reflected by XIAP protein expression can identify such carriers and the analysis of NOD2 signaling by flow cytometry can confirm the functional significance. XIAP expression patterns should be investigated in female patients with a family history of EN and/or IBD.
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Acknowledgments
Prof. Stephan Ehl from the CCI in Freiburg, who pointed us towards the possible involvement of XIAP in this family. We sincerely thank all our patients and their family members who made this study possible and the referring consultants (Dr Claire Dolling and Dr Yusuf Karim) for their help. We also thank the technicians of the Center of Chronic Immunodeficiency Advanced Diagnostic for excellent technical assistance.
Funding
This study was supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803 and and BMBF 01GM1111B). The authors are responsible for the contents of this publication.
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The authors have no conflicts of interest.
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Magdalena Dziadzio, Sandra Ammann, Carsten Speckmann and Bodo Grimbacher contributed equally and are considered aequo loco.
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Figure S1
Colonic biopsies from index patient V.24 A) Pre-BMT: H&E staining of the large bowel mucosa with preservation of crypt architecture. There is patchy active inflammation and focal increase in mixed inflammatory cells in the lamina propria; no granulomas. The appearance is consistent with mild focal active colitis. B): Post-BMT: H&E staining of the large bowel mucosa showing hypocellularity of the lamina propria and some mild distortion of the crypt architecture. There is no evidence of GVHD and no viral inclusions. (JPEG 115 kb)
Table S1
Summary of the phenotypes of patients and carriers. (DOCX 20 kb)
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Dziadzio, M., Ammann, S., Canning, C. et al. Symptomatic Males and Female Carriers in a Large Caucasian Kindred with XIAP Deficiency. J Clin Immunol 35, 439–444 (2015). https://doi.org/10.1007/s10875-015-0166-0
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DOI: https://doi.org/10.1007/s10875-015-0166-0