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Updated: Jun 21, 2026
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
Phenotypic differences between mice deficient in XIAP and SAP, two factors targeted in X-linked lymphoproliferative
Julie M Rumble1, Karolyn A Oetjen, Paul L Stein
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Abstract:
Mutations in the X-linked inhibitor of apoptosis (XIAP) have recently been identified in patients with the rare genetic disease, X-linked lymphoproliferative syndrome (XLP), which was previously thought to be solely attributable to mutations in a distinct gene, SAP. To further understand the roles of these two factors in the pathogenesis of XLP, we have compared mice deficient in Xiap with known phenotypes of Sap-null mice. We show here that in contrast to Sap-deficient mice, animals lacking Xiap have apparently normal NKT cell development and no apparent defect in humoral responses to T cell-dependent antigens. However, Xiap-deficient cells were more susceptible to death upon infection with the murine herpesvirus MHV-68 and gave rise to more infectious virus. These differences could be rescued by restoration of XIAP. These data provide insight into the differing roles of XIAP and SAP in the pathogenesis of XLP.
Insights
Mutations in X-linked inhibitor of apoptosis (XIAP) are linked to X-linked lymphoproliferative syndrome (XLP). Xiap-deficient mice showed increased susceptibility to viral infection, unlike Sap-deficient mice, highlighting XIAP
Area of Science:
- Immunology
- Genetics
- Virology
Background:
- X-linked lymphoproliferative syndrome (XLP) is a rare genetic disorder.
- Mutations in SAP were previously the only known cause of XLP.
- Recent findings link X-linked inhibitor of apoptosis (XIAP) mutations to XLP.
Purpose of the Study:
- To compare the roles of XIAP and SAP in XLP pathogenesis.
- To investigate the function of XIAP in immune responses.
- To understand the differential contributions of XIAP and SAP to XLP.
Main Methods:
- Generation and analysis of Xiap-deficient mice.
- Comparison of Xiap-null mice with existing Sap-null mouse models.
- Assessment of NKT cell development and humoral immune responses.
- Evaluation of susceptibility to murine herpesvirus (MHV-68) infection.
- Rescue experiments by XIAP restoration.
Main Results:
- Xiap-deficient mice exhibited normal NKT cell development.
- No apparent defects in humoral responses to T cell-dependent antigens were observed in Xiap-deficient mice.
- Xiap-deficient cells showed increased susceptibility to MHV-68 infection and higher viral output.
- These defects were reversible upon XIAP restoration.
Conclusions:
- XIAP and SAP play distinct roles in XLP pathogenesis.
- XIAP is crucial for controlling viral infections, particularly MHV-68.
- XIAP's role in XLP differs from that of SAP, particularly in viral defense mechanisms.
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