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T. M. Martin, C. R. Austin, T. M. Doyle, K. A. Goodwin, C. D. Rosé, F. Foster, C. S. Foster; Identification of a Novel Mutation in the Blau Syndrome Gene, NOD2, in a Large Family With Inherited Uveitis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3746.
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To determine if the severe uveitis that is highly penetrant in a large family may be associated with mutation in NOD2 (CARD15). Mutations in NOD2 are known to cause another form of familial uveitis, Blau syndrome.
Available ophthalmic examinations, clinical course of uveitis, and medical history of affected family members were documented. Genotyping of NOD2 coding regions was performed on genomic DNA by PCR amplification and direct sequencing in both directions. This research was conducted under human subjects protocols approved by the investigators’ ethics committees.
The pedigree consisted of 64 individuals in 3 generations (including spouses of family members). In the 1st living generation, 4 out of 9 siblings were affected by uveitis. The uveitis presented in young adulthood and followed a course of bilateral, recurrent, non-granulomatous inflammation. In some individuals the uveitis was anterior and in others it was a panuveitis. None of the affected family members developed arthritis in childhood or have ever developed psoriasis. Systemic therapy was necessary to control the uveitic inflammation. In the 2nd generation, 3 out of 15 offspring of affected siblings were known to be affected. None of the 1st generation unaffected siblings had any affected children (n=15). There were 7 individuals in the 3rd generation, all unaffected thus far. Given that several family members are children, it is possible that some may yet develop uveitis. All 9 individuals in the 1st generation were genotyped. All of the affected and none of the unaffected siblings were heterozygous for a novel mutation in exon 4, predicted to encode a glutamate to alanine substitution at amino acid 600 (E600A). While all 9 siblings were homozygous for a common polymorphism at arginine 587, no other disease-associated mutations were found. The E600A mutation has not previously been identified in Blau syndrome nor is it a known polymorphism. NOD2 genotyping has confirmed the mutation in the 3 affected 2nd generation individuals, as well as in 5 other family members (all children and offspring of an affected individual).
This is the first time that a NOD2 mutation encoding E600A has been implicated in disease. Unlike Blau syndrome, this family exhibits non-granulomatous uveitis in the absence of systemic disease. These findings suggest that the clinical spectra of NOD2 mutational effects be expanded to include rare (non-Blau syndrome) forms of severe, inherited uveitis.
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