Blau Syndrome-Related CARD15/NOD2 Mutations Are Not Linked to Idiopathic Uveitis in Spanish Patients

Abstract

Abstract. Uveitis is a clinical feature of the Blau syndrome, a disease linked to CARD15 (also referred to as NOD2) mutations. Three main mutations in this gene (R334W, R334Q and L469F) have been reported as Blau syndrome risk factors, a disease that manifests uveitis as one of its clinical features. However, little is known on the involvement of this gene in idiopathic uveitis. We thus sought to determine the frequency of these Blau-related CARD15 mutations in a cohort of Spanish patients with idiopathic uveitis. To this aim, 110 patients with idiopathic uveitis, followed at the Department of Ophtalmology of a tertiary hospital (Hospital Universitario Alcalá de Henares, Madrid. Spain) were enrolled. As a control population, 104 healthy subjects were used. DNA was extracted from blood samples and the Blau-related CARD15 mutations were analysed either by PCR-RFLP or direct DNA sequencing. None of the mutations studied was found in any of the individuals tested, whether diseased or healthy. It seems thus that Blau syndrome-related CARD15 mutations are not involved in idiopathic uveitis, a finding which allows us to suggest that the genetic aetiology of the idiopathic uveitis or the Blau-associated uveitis is different.

The common NOD2/CARD15 variant P268S in patients with non-infectious uveitis: a cohort study

“…In contrast to previous reports [ 11 , 12 ], our study, showed a statistical association between the variant P268S/SNP5 (SNP rs2066842) and ACU, both idiopathic and associated with other rheumatic disease. In our cohort the incidence of variations was not significantly different between our patients with idiopathic chronic uveitis and those with chronic uveitis associated to auto-immune diseases.…”

“…The role of NOD2/CARD15 gene as a key regulator of innate immunity in the eye has been elucidated by studies performed on murine models,which are knockout for NOD2/CARD15, which showed an increased susceptibility to uveitis [ 9 , 10 ]. However the first reports conducted on patients affected by idiopathic uveitis has failed to demonstrate a role for this gene in this disease; two studies conducted on a large cohort of spanish patients with idiopathic uveitis suggested that NOD2/CARD15 variants do not seem to predispose to thee disease [ 11 , 12 ]. In order to investigate the possible role of this gene in ACU, we have studied NOD2/CARD15 variants and the genotype-phenotype correlation in a cohort of patients with idiopathic uveitis and uveitis associated with other inflammatory diseases.…”

“…Other studies trying to link NOD2 mutations and non-infectious chronic uveitis failed to show any association, with the remarkable exception of the Blau related ones. In particular, Rodriguez-Perez and colleagues [ 10 , 11 ], in their cohort of more than 100 patients with idiopathic chronic uveitis, reported allele frequencies as high as 50 % for the variant P268S, 7 % for the mutation R702W and 2 % for the mutation G908R while none of the mutations responsible for Blau syndrome (R334W, R334Q and L469F) was found in any of the individuals tested. When the frequency of the different mutations in the group of patients was compared to that of 104 healthy subjects, no statistical differences were found and the authors concluded that none of the CARD15 mutations linked to Crohn's Disease was involved in the pathogenesis of idiopathic uveitis.…”

Gene mutations and clinical phenotypes in Chinese children with Blau syndrome

“…So far, more than 10 mutations in CARD15 which are closely associated with the disease have been reported in different races and regions. R334Q and L469F were the earliest discovered mutations (Miceli-Richard et al, 2001), and R334W and R334Q were the most frequently found mutations, which were observed in more than 50% of patients (Milhavet et al, 2008;Rodriguez-Perez et al, 2009) (Milman et al, 2009). Further studies of the sporadic cases of Blau syndrome revealed more mutations, such as D382E, E383G, G464W, G481D, W490L, C495Y, H496L, M513T, R587C, T605P, A612T, and N670K.…”

Inborn errors E778K and G908R in NOD2 gene increase risk of nontuberculous mycobacterial infection: a computational study

“…It has been shown that the polymorphisms in the NOD2 gene are associated with the occurrence of some infectious diseases and granulomatous inflammation, including mycobacterium tuberculosis 13 , Crohn’s disease 14 , and Blau’s syndrome 15–17 .…”