Autoimmune Lymphoproliferative Syndrome with Somatic Fas Mutations

Charles University in Prague, Praha, Praha, Czech Republic
New England Journal of Medicine (Impact Factor: 55.87). 10/2004; 351(14):1409-18. DOI: 10.1056/NEJMoa040036
Source: PubMed


Impaired Fas-induced apoptosis of lymphocytes in vitro is a principal feature of the autoimmune lymphoproliferative syndrome (ALPS). We studied six children with ALPS whose lymphocytes had normal sensitivity to Fas-induced apoptosis in vitro.
Susceptibility to Fas-mediated apoptosis and the Fas gene were analyzed in purified subgroups of T cells and other mononuclear cells from six patients with ALPS type III.
Heterozygous dominant Fas mutations were detected in the polyclonal double-negative T cells from all six patients. In two patients, these mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells.
Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death.

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Available from: Frédéric Rieux-Laucat, Oct 03, 2015
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    • "In case 17, a 4.8-Mb deletion at 10q23.31q23.33 was identified that includes MIR107 and FAS (Figure 3B). MIR107 plays a role in inhibiting differentiation in granulocytic, monocytic, and B-lymphoid lines [32], whereas FAS is involved with apoptosis, and mutations in FAS are known to cause autoimmune lymphoproliferative syndrome [33]. Cases 25 and 32 had a deletion at 3p21.31 of 2.2 Mb and 3.06 Mb, respectively, that included CDC25A (Figure 3C), which is required for progression from G1 to S phase in the cell cycle [34]. "
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    • "It is of considerable importance that genetic analysis of blood samples may not reveal somatically-occurring sequence alterations in the diseased cardiac tissues, but these mutations may provide a molecular rationale for pathogenesis [14,15]. We recently reported evidence for somatically-derived NKX2-5 and TBX5 mutations as a novel mechanism for septation defects of the human heart [16-18], and used the same heart collection of malformed hearts to investigate GATA4 gene mutations, notably those affecting the coding of amino acids for zinc finger functions of the protein [19]. "
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    • "Ce syndrome est lié à des mutations du gène FOX P3 qui code pour l'ADNbinding protein scurfin nécessaire à l'activité des lymphocytes T régulateurs CD4+, CD25+ [19] [20] ; ● le syndrome ALPS (autoimmune lymphoproliferative syndrome ) se caractérise par des mutations du système FAS/ FAS Ligand régulant l'apoptose lymphocytaire. Ce syndrome , dont il existe plusieurs formes, se caractérise globalement par des manifestations auto-immunes cliniques et biologiques (cytopénies) et l'apparition d'une lymphoprolifération CD4–/CD8– [21] ; ● le syndrome APECED (autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy syndrome) appelé aussi APS-1 (autoimmune polyendocrine syndrome-1) est caractérisé par les mutations du gène AIRE (auto-immune regulator proteine) qui intervient dans l'éducation thymique des lymphocytes T régulateurs. Ce syndrome se caractérise par des manifestations auto-immunes essentiellement endocriniennes parfois associées à une candidose chronique [22]. "
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