Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis
| Autor: | Wilco de Jager, Angelo Ravelli, Nico M Wulffraat, Richard van Wijk, Elisabetta Cortis, Fabrizio De Benedetti, Berent J. Prakken, Wietse Kuis, Silvia Magni-Manzoni, Wouter W. van Solinge, L E D'Urbano, Karen M.K. de Vooght, Sebastiaan J. Vastert, Antonella Insalaco |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Cytotoxicity
Immunologic Cytotoxicity Arthritis Adolescent Arthritis Juvenile Rheumatoid complications/immunology Cells Cultured Child Child Preschool Cytotoxicity Immunologic Genetic Predisposition to Disease Genotype Humans Infant Killer Cells Natural immunology Macrophage Activation Syndrome etiology/genetics/immunology Mutation Pore Forming Cytotoxic Proteins biosynthesis/genetics Promoter Regions Genetic Transfection biosynthesis/genetics medicine.disease_cause immunology Immunologic Missense mutation Killer Cells Pharmacology (medical) Child Promoter Regions Genetic Cells Cultured Mutation Cultured biology Macrophage Activation Syndrome Killer Cells Natural medicine.anatomical_structure Child Preschool Pore Forming Cytotoxic Proteins complications/immunology Adolescent Genotype Cells Transfection Natural killer cell Promoter Regions Rheumatology Genetic medicine Humans Genetic Predisposition to Disease Preschool business.industry Perforin Infant medicine.disease Systemic-onset juvenile idiopathic arthritis Arthritis Juvenile etiology/genetics/immunology Macrophage activation syndrome Immunology biology.protein business Juvenile rheumatoid arthritis |
| Zdroj: | Rheumatology (Oxford, England). 49(3) |
| ISSN: | 1462-0332 |
| Popis: | Objective Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS. Methods DNA of 56 SoJIA patients (41 Italian and 15 Dutch) was isolated. Of these, 15 (27%) had a confirmed history of MAS. We sequenced PRF1 and 1.5 kb of the 5'-upstream region. DNA sequence variations in the promoter region were functionally tested in transfection experiments using a human NK cell line. Results We detected a previously undescribed sequence variation (-499 C > T) in the promoter of PRF1 in 18% of the SoJIA patients. However, transfection experiments did not show functional implications of this variation. Secondly, we found that 11 of 56 (20%) SoJIA patients were heterozygous for missense mutations in PRF1. In particular, we found a high prevalence of the Ala91Val mutation, a variant known to result in defective function of perforin. Interestingly, the prevalence of Ala91Val in SoJIA patients with a history of MAS (20%) was increased compared with SoJIA patients without MAS (9.8%). One SoJIA patient, heterozygous for Ala91Val, showed profound decreased perforin levels at the time of MAS. Conclusions These findings suggest that PRF1 mutations play a role in the development of MAS in SoJIA patients. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|