Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype
| Autor: | Irma Dianzani, Maurizio Aricò, Matteo Melensi, Ugo Ramenghi, Umberto Dianzani, Annalisa Chiocchetti, Elena Boggio |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_treatment Down-Regulation X-Linked Inhibitor of Apoptosis Protein Hematopoietic stem cell transplantation Caspase 8 Inhibitor of apoptosis Immunophenotyping Arthritis Rheumatoid Fatal Outcome medicine Genes Overlapping Humans UNC13D fas Receptor Child business.industry Autoimmune Lymphoproliferative Syndrome Membrane Proteins Familial Hemophagocytic Lymphohistiocytosis medicine.disease Fas receptor XIAP Pedigree fas gene autoimmune lymphoproliferative syndrome Autoimmune lymphoproliferative syndrome Pediatrics Perinatology and Child Health Immunology Mutation Female business |
| Zdroj: | Pediatrics. 132(4) |
| ISSN: | 1098-4275 |
| Popis: | This article presents a case report for a child presenting with mixed clinical features of autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis (FHL), and X-linked lymphoproliferative (XLP) disease. From 6 months, he exhibited splenomegaly and lymphoadenopathy and from 4 years, he showed recurrent severe autoimmune hemocytopenia and sepsislike bouts of fever, from which he eventually died at the age of 12. Intriguingly, the patient carried mutations in FAS , XIAP , and UNC13D genes, which are involved in ALPS, XLP disease, and FHL, respectively. These mutations were inherited from the mother, who had rheumatoid arthritis but no signs of ALPS. A role for other modifying genes was suggested by the finding that the healthy father exhibited defective Fas function, without mutation of the FAS gene, and had transmitted to the patient an osteopontin ( OPN ) gene variant previously associated with ALPS. Therefore, several genes might influence the disease outcome in this family. In vitro analyses revealed that the FAS and the XIAP mutations decreased expression of the corresponding proteins, and the UNC13D mutation decreased granule secretion and Munc interaction with Rab-27a. These findings suggest that overlap may exist between ALPS, FHL, and XLP disease, in accordance with the notion that FHL and XLP disease are due to defective natural killer (NK)/NK T–cell function, which involves Fas. Therefore, we propose that NK cell defects should be evaluated in patients with ALPS-like characteristics, and hematopoietic stem cell transplantation should be considered in individuals with severe refractory cytopenia and FHL-like manifestations. * Abbreviations: ALPS — : autoimmune lymphoproliferative syndrome FHL — : familial hemophagocytic lymphohistiocytosis HMC-1 — : human mast cell 1 NK — : natural killer PBMC — : peripheral blood mononuclear cell SNP — : single-nucleotide polymorphism WB — : Western blotting wt — : wild-type XIAP — : X-linked inhibitor of apoptosis XLP — : X-linked lymphoproliferative |
| Databáze: | OpenAIRE |
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