title: Differential regulation of miR-146a/FAS and miR-21/FASLG axes in autoimmune lymphoproliferative syndrome due to FAS mutation (ALPS-FAS).
abstract: Most cases of autoimmune lymphoproliferative syndrome (ALPS) have an inherited genetic defect involving apoptosis-related genes of the FAS pathway. MicroRNAs (miRNAs) are a class of small non-coding regulatory RNAs playing a role in the control of gene expression. This is the first report on miRNAs in ALPS patients. We studied a mother and son carrying the same FAS cell surface death receptor (FAS) mutation, but with only the son manifesting the signs and symptoms of ALPS-FAS. The aim was to analyse, by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), the peripheral blood mononuclear cells (PBMC) relative expression of miR-146a and miR-21, including their passenger strands and respective targets (FAS and FASLG). In comparison with healthy matched control individuals, miR-21-3p was over-expressed significantly (P = 0·0313) in the son, with no significant change in the expression of miR-146a, miR-146a-3p and miR-21. In contrast, the mother had a slight under-expression of the miR-146a pair and miR-21-3p (P = 0·0625). Regarding the miRNA targets, FAS was up-regulated markedly for the mother (P = 0·0078), but down-regulated for the son (P = 0·0625), while FASLG did not have any significant alteration. Taken together, our finding clearly suggests a role of the miR-146a/FAS axis in ALPS-FAS variable expressivity in which FAS haploinsufficiency seems to be compensated only in the mother who had the miR-146a pair down-regulated. As only the son had the major clinical manifestations of ALPS-FAS, miR-21-3p should be investigated as playing a critical role in ALPS physiopathology, including the development of lymphoma.
authors.affiliation: Laboratory of Pediatric Immunology, Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas - UNICAMP, Campinas, SP, Brazil.
authors.forename: Lia Furlaneto
authors.initials: LF
authors.lastname: Marega
authors.affiliation: Laboratory of Pediatric Immunology, Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas - UNICAMP, Campinas, SP, Brazil.
authors.forename: Marcelo Ananias
authors.initials: MA
authors.lastname: Teocchi
authors.affiliation: Laboratory of Pediatric Immunology, Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas - UNICAMP, Campinas, SP, Brazil.
authors.forename: Maria Marluce
authors.initials: MM
authors.lastname: Dos Santos Vilela
mesh_terms: D000328:Adult; D017209:Apoptosis; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000503:physiopathology; D015536:Down-Regulation; D053222:Fas Ligand Protein / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C542542:MIRN146 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D019014:fas Receptor
keywords: apoptosis; gene expression regulation; immunologic deficiency syndromes