Systemic Juvenile Idiopathic Arthritis (SJIA) is associated with macrophage activation syndrome (MAS). MAS bears close resemblance to familial hemophagocytic lymphohistiocytosis (FHLH). The development of FHLH has been recently associated with mutations in MUNC13-4 gene. The purpose of this study was to assess for possible sequence alterations in MUNC13-4 gene in SJIA/MAS.
MUNC13-4 sequence was analyzed in 18 unrelated patients with SJIA/MAS using 32 primer pair sets designed to amplify the 32 exons and at least 100 base pairs of the adjacent intronic regions. DNA samples from unrelated 73 SJIA patients without MAS history and 229 healthy unrelated individuals were used as controls.
Bi-allelic sequence variants in MUNC13-4 gene reported in FHLH were present in two of 18 patients. Further analysis of the MUNC13-4 sequences revealed an identical combination of 12 single nucleotide polymorphisms (SNP) in 9 of remaining 16 SJIA/MAS patients (57%). Additional analysis suggested that these 12 SNPs [154(-19)g>a, 261(+26)c>g, 388(+81)g>a, 388(+122)c>t, 570(-60)t>g, 888G>C, 1389(+36)g>a, 1992(+5)g>a, 2447(+144)c>t, 2599A>G, 2830(+37)c>g, 3198A>G] were inherited as an extended haplotype. In several patients, in addition to the described haplotype, there were other SNPs in the second allele of the MUNC13-4 gene. Moreover, one patient had a complex mutation with two changes, 2542A>C and 2943G>C in a cis configuration. The haplotype was present only in 27 of 229 (12%) healthy controls (Chi Square =23.5) and in 6 of 73 (8.2 %) SJIA patients without MAS history.
The data suggest an association between MUNC13-4 gene polymorphisms and MAS in SJIA.
Keywords: juvenile idiopathic arthritis, Still’s disease, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, MUNC13-4 gene, SNP polymorphism