Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor- B activation: common genetic etiology with Blau syndrome

Abstract

Early-onset sarcoidosis (EOS) and inheritable Blau syndrome (BS) share characteristic clinical features of juvenile-onset systemic granulomatosis syndrome that mainly affects skin, joints, and eyes. However, no direct evidence has been shown for the possible common origin of these 2 diseases. Recent discovery of CARD15 mutations in BS families encouraged us to investigate similar CARD15 mutations in EOS patients. Among 10 EOS cases retrospectively collected in Japan, heterozygous missense mutations were found in 9 cases; 4 showed a 1000C>T (R334W in amino acid change) that has been reported in BS, 4 showed novel 1487A>T (H496L) , IntroductionSarcoidosis is a multiorganic inflammatory disease with unknown etiology, characterized by the histologic features of noncaseating epithelioid granulomas. In childhood, 2 distinct types of sarcoidosis have been described. 1 Usually the disease is detected in older children by chest radiography and the clinical manifestations are characterized by a classical triad of lung, lymph node, and eye involvement, similar to those in adults. In contrast, early-onset sarcoidosis (EOS), which usually appears in those younger than 4 years of age, is quite rare and has a distinct triad of skin, joint, and eye disorders, without apparent pulmonary involvement. Compared with an asymptomatic and sometimes naturally disappearing course of the disease in older children, EOS is progressive and in many cases causes severe complications, such as blindness, joint destruction, and visceral involvement. 2 Blau syndrome (BS), also showing early-onset granulomatous arthritis, uveitis, and skin rash, is a rare familial disease transmitted in an autosomal dominant manner. 3 By linkage analysis, the responsible locus for BS was mapped to chromosome 16,4 in which CARD15 has recently been identified as the susceptibility gene. 5 CARD15 (NOD2) is a member of the growing family of nucleotide-binding oligomerization domain (NOD) proteins and composed of 2 amino-terminal caspase recruitment domains (CARDs), one NOD, and carboxy-terminal leucinerich repeats (LRRs). 6,7 While mutations in LRRs are reportedly associated with Crohn disease (CD) and psoriatic arthritis, 8-10 3 types of missense point mutations in the NOD, 1000CϾT (R334W in amino acid change), 1001GϾA (R334Q), and 1405CϾT (L469F), have been discovered in BS families. 5,11,12 It has been discussed since the first report of BS whether EOS and BS are the same diseases. 13 However, no direct evidence of their common origin has been shown and confusion still remains. 14 In the first paper describing genetic abnormalities in BS, the authors recognized no CARD15 mutation in 2 EOS patients and therefore proposed a different etiology of BS and EOS. 5 However, we have recently described a sporadic case of systemic granulomatosis syndrome with clinical features of EOS that showed the same CARD15 mutation as detected in BS. 15 In this report, therefore, we retrospectively collected Japanese EOS cases and searched for CARD15 mutations, to further evaluate the re...

RIP kinases: key decision makers in cell death and innate immunity

“…[152][153][154] Lossof-function mutations in NOD2 are associated with greatly increased susceptibility to Crohn's disease, [155][156][157] whereas gain-of-function mutations are linked to early onset sarcoidosis and Blau syndrome. 158,159 NOD2 contains an N-terminal CARD domain, a central NACHT region and C-terminal LRRs. 160 Upon binding of MDP to the LRRs of NOD2, the NACHT regions are exposed, allowing for self-oligomerization of NOD2 molecules, followed by homotypic interactions between the CARD domains of NOD2 and RIP2 161,162 (Figure 4).…”

Enhanced NF‐κB activation with an inflammasome activator correlates with activity of autoinflammatory disease associated with NLRP3 mutations outside of exon 3: Comment on the article by Jéru et al

“…For NOD2, gain-of-function mutations associated with granulomatous disorders are recognized in the centrally located NOD and exhibit similar spontaneous activation of NF-B without the NOD2 ligand (6). Interestingly, the amino acids affected by an R260W mutation in NLRP3 and an R334W mutation in NOD2 are at analogous positions, suggesting a common molecular mechanism for development of autoinflammatory disease.…”

A Novel Mutation in Helical Domain 2 of NOD2 in Sporadic Blau Syndrome

“…The E667K mutation was located in helical domain 2 of the nucleotide binding and oligomerization (NACHT) region, which is required for NOD2 funtion. The E667K is in close proximity to another mutation in the NACHT region, an asparagine to lysine substitution at position 670 (N670K) that was shown to be associated with EOS 4 . E667 is conserved across species and therefore seems to be a critical residue (Figure 2D).…”