Autoimmune lymphoproliferative syndrome caused by homozygous FAS mutations with normal or residual protein expression Nourhen Agrebi, PhD, Lamia Sfaihi.

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Presentation transcript:

Autoimmune lymphoproliferative syndrome caused by homozygous FAS mutations with normal or residual protein expression Nourhen Agrebi, PhD, Lamia Sfaihi Ben-Mansour, MD, Moez Medhaffar, MD, Sondes Hadiji, MD, Faten Fedhila, MD, Meriem Ben-Ali, MD, Najla Mekki, MD, Mongia Hachicha, MD, Sihem Barsaoui, MD, Mohamed-Ridha Barbouche, MD, PhD, Imen Ben-Mustapha, MD Journal of Allergy and Clinical Immunology Volume 140, Issue 1, Pages 298-301.e3 (July 2017) DOI: 10.1016/j.jaci.2016.11.033 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Homozygous FAS mutations identified in 2 consanguineous kindreds. A, Family pedigrees. Affected patients are indicated with an arrow. B and C, Genomic sequence analysis of the FAS gene showing intracellular (c.1017A>G; Fig 1, B) and extracellular (c.581C>T; Fig 1, C) homozygous substitutions. Both parents are heterozygous. D, Multiple protein alignment showing the position of the conserved N266 and R121 residues in different species. Mutated residues are indicated with an arrow. CRD, Cysteine-rich domain; P, patient. Journal of Allergy and Clinical Immunology 2017 140, 298-301.e3DOI: (10.1016/j.jaci.2016.11.033) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Functional characterization of the 2 homozygous FAS mutations. A, Fas surface expression on PBMCs, as determined by using flow cytometry with anti-CD95 mAb. B, Quantification of the absolute number of Fas molecules on the cell surfaces of EBV-transformed B cells by using the QuantiBRITE PE assay (BD Biosciences, San Jose, Calif) (n = 3 controls). C, Fas-induced apoptosis in EBV-transformed B cells stimulated for 24 hours with or without APO-1-3 (Enzo Life Sciences, Farmingdale, NY) in the presence of protein A for 20 minutes. Data represent 2 separate experiments. D, Fas-associated death domain (FADD) recruitment in EBV-transformed B cells. The T bars indicate the SD. Statistical analyses were done with the Student t test. *P < .05 and **P < .01. Ctrl, Control; IP, immunoprecipitation; P, patient; WB, Western blot. Journal of Allergy and Clinical Immunology 2017 140, 298-301.e3DOI: (10.1016/j.jaci.2016.11.033) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Percentage of CD95 expression in 40 healthy control subjects, homozygous patients, and heterozygous parents for N266S and R121W mutations. The dashed line indicates the fifth percentile of Fas expression percentage in healthy control subjects. Journal of Allergy and Clinical Immunology 2017 140, 298-301.e3DOI: (10.1016/j.jaci.2016.11.033) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions