OBJECTIVE: Systemic
juvenile idiopathic arthritis (JIA) is associated with
macrophage activation syndrome.
Macrophage activation syndrome bears a close resemblance to familial
hemophagocytic lymphohistiocytosis (
HLH). The development of familial
HLH has been recently associated with
mutations in MUNC13-4. The purpose of this study was to assess for possible sequence alterations in MUNC13-4 in patients with systemic JIA/
macrophage activation syndrome. METHODS: The MUNC13-4 sequence was analyzed in 18 unrelated patients with systemic JIA/
macrophage activation syndrome, using 32 primer pair sets designed to amplify the 32
exons and at least 100 basepairs of the adjacent
intronic regions.
DNA samples obtained from 73 unrelated patients with systemic JIA and no history of
macrophage activation syndrome and 229 unrelated healthy individuals were used as controls. RESULTS: The biallelic sequence variants in MUNC13-4 reported in familial
HLH were present in 2 of the 18 patients with JIA/
macrophage activation syndrome. Further analysis of the MUNC13-4 sequences revealed an identical combination of 12
single-nucleotide polymorphisms (
SNPs) in 9 of the remaining 16 patients with systemic JIA/
macrophage activation syndrome (56%). 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, 888 G>C, 1389[+36] g>a, 1992[+5] g>a, 2447[+144] c>t, 2599 A>G, 2830[+37] c>g, 3198 A>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 MUNC13-4. Moreover, 1 patient had a complex
mutation with 2 changes, 2542 A>C and 2943 G>C, in a
cis configuration. The
haplotype was present in only 27 (12%) of 229 healthy control subjects (chi(2) = 23.5) and in 6 (8.2%) of 73 patients with systemic JIA and no history of
macrophage activation syndrome. CONCLUSION: The data suggest an association between MUNC13-4 polymorphisms and
macrophage activation syndrome in patients with systemic JIA.
