Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation - PubMed (original) (raw)

Case Reports

. 2013 Feb;131(2):486-90.

doi: 10.1016/j.jaci.2012.06.011. Epub 2012 Jul 31.

Marie-Claude Stolzenberg, Nina Lanzarotti, Bénédicte Neven, Cécile Daussy, Capucine Picard, Nathalie Neveux, Mukesh Desai, Meghana Rao, Kanjaksha Ghosh, Manisha Madkaikar, Alain Fischer, Frédéric Rieux-Laucat

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Case Reports

Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation

Aude Magerus-Chatinet et al. J Allergy Clin Immunol. 2013 Feb.

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.

Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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Figures

FIG 1

FIG 1

Massive tumor syndrome in the patient with ALPS-FASLG. A, At 8 months of age, the patient showed massive hepatosplenomegaly. B, A chest radiograph obtained at the age of 11 months highlighted mediastinal enlargement caused by persistent lymph nodes.

FIG 2

FIG 2

Family pedigree of the patient with ALPS-FASLG. E?, DNA material unavailable.

FIG 3

FIG 3

The FASLG mutation and its effect on the expression and function of FAS ligand protein. A, Sequencing profiles of genomic FASLG exon 1 obtained from blood cells. B and C, RT-PCR products of FASLG and hypoxanthine phosphoribosyltransferase (HPRT) amplified from cDNA (Fig 3, B) or immunoblots of FAS ligand and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from protein lysates of activated T cells reactivated (+) or not (−; Fig 3, C). D, A functional apoptosis assay was performed on activated T cells from a healthy control subject, the patient, the patient’s relatives, and a patient with ALPS carrying a homozygous null FAS mutation (ALPS-FAS-HMZ). The histogram is representative of 3 independent experiments.

FIG 4

FIG 4

Schema of the location of the 4 FASLG mutations described to date in human subjects and comparison of biological characteristics of the 4 patients. Heterozygous and homozygous mutations are depicted in blue or red, respectively. The table summarizes the main biological characteristics of the 4 patients. SLE, Systemic lupus erythematosus; TM, transmembrane domain.

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