Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation - 30/01/13
, Marie-Claude Stolzenberg, PhD a, b, Nina Lanzarotti, MD a, b, Bénédicte Neven, MD, PhD a, b, c, Cécile Daussy a, b, Capucine Picard, MD, PhD b, c, d, e, Nathalie Neveux, PharmD, PhD f, Mukesh Desai, MD g, Meghana Rao, MD h, Kanjaksha Ghosh, MD h, Manisha Madkaikar, MD h, Alain Fischer, MD, PhD a, b, c, Frédéric Rieux-Laucat, PhD a, b, c
Corresponding author: Aude Magerus-Chatinet, PhD, INSERM U768, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, F-75015 Paris, France.Abstract |
Background |
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphoproliferation, accumulation of double-negative T cells, hypergammaglobulinemia G and A, and autoimmune cytopenia.
Objectives |
Although mostly associated with FAS mutations, different genetic defects leading to impaired apoptosis have been described in patients with ALPS, including the FAS ligand gene (FASLG) in rare cases. Here we report on the first case of complete FAS ligand deficiency caused by a homozygous null mutant.
Methods |
Double-negative T-cell counts and plasma IL-10 and FAS ligand concentrations were determined as ALPS markers. The FASLG gene was sequenced, and its expression was analyzed by means of Western blotting. FAS ligand function was assessed based on reactivation-induced cell death.
Results |
We describe a patient born to consanguineous parents who presented with a severe form of ALPS caused by FASLG deficiency. Although the clinical presentation was compatible with a homozygous FAS mutation, FAS-induced apoptosis was normal, and plasma FAS ligand levels were not detectable. This patient carries a homozygous, germline, single-base-pair deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation, confirming its recessive trait.
Conclusion |
FAS ligand deficiency should be screened in patients presenting with ALPS features but lacking the usual markers, including plasma soluble FAS ligand and an in vitro apoptotic defect. An activation-induced cell death test could help in discrimination.
Le texte complet de cet article est disponible en PDF.Key words : Autoimmune lymphoproliferative syndrome, Fas ligand, diagnosis
Abbreviations used : AICD, ALPS, DN, FASLG, MMF, TSST-1, WBC
Plan
| Supported by grants from INSERM, Agence Nationale de la Recherche (ANR; grant no. 08-GENO-015-01), the E-Rare 2007 programme (EPINOSTICS), the Ligue National Contre le Cancer, the European STREP (AUTOROME), and an advanced grant from the European Research Council (ERC). A.M.-C. was funded by the European STREP, the Centre de Référence des Déficits Immunitaires Héréditaires (CEREDIH) and the ERC. N.L. was awarded a doctoral fellowship by INSERM. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 2
P. 486-490 - février 2013 Retour au numéro
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