The NOD2 gene is located on chromosome 16 at 16q12.1 and encodes the nucleotide-binding oligomerization domain-containing protein 2, a member of the NOD-like receptor family. NOD2 is a cytoplasmic pattern recognition receptor and plays an important role in regulating the innate immune response. The NOD2 gene was first reported in relation to autosomal dominant Blau syndrome in 2001 (Miceli-Richard et al., PMID 11528384). At least 20 unique missense variants have been reported in clinical cases with up to 80% of Blau syndrome associated with two recurrent NOD2 variants: p.Arg334Trp and p.Arg334Gln (Cantarini et al., 2014 PMID 25182201). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data.
Variants in this gene have been reported in at least nineteen probands in twelve publications (Hugot et al., 2001 PMID 11528384; Miyachi et al., 2005 15459013; Nakahata et al., 2009 PMID 19116920; Wouters et al., 2009 PMID 19479837; Shen et al., 2017 PMID 28721627; Williams et al., 2002 PMID 12428248; Santos-Juanes et al., 2007 PMID 17916199; Cirak et al., 2010 PMID 20084402; Pramono et al., 2019 PMID 31543536; Li et al., 2019 PMID 31803699; Nielsen et al., 2016 PMID 17207093). Wang et al. (2002 PMID 12428248) performed linkage analysis on ten families with Blau syndrome and reported a combined LOD score of 5.67. De novo variants have also been reported. The mechanism of disease is unknown. In vitro experiments suggest variants lead to a gain of function and ligand independent activation of NOD2 (Monie et al., 2014 PMID 25093298); however, patient cell and mouse model data suggest a downregulation of NOD2 signalling pathways. This gene-disease association is supported by data from patient cells which point to a disruption of NOD2 signalling pathways (Rosenbaum et al., 2011 PMID 21296813; Lee et al., 2010 PMID 20052476; Saito et al., 2017 PMID 28587749). Mouse models also showed partial recapitulation of aspects of disease (Davey et al., 2015; PMID 21296813). In summary, NOD2 is definitively associated with autosomal dominant Blau syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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