Mutation of LACC1 is associated with a Monogenic Form of Systemic Juvenile Idiopathic Arthritis.

Objective. The pathological basis of systemic juvenile idiopathic arthritis (sJIA) is somewhat controversial with arguments for both autoimmune and autoinflammatory etiologies. Several monogenic autoinflammatory disorders have been described but thus far sJIA has only been attributed to mutation of MEFV in rare cases and has been weakly associated with the HLA class II locus. The aim of this study was to identify the cause of an autosomal recessive form of sJIA. Methods. We studied 13 sJIA patients from 5 consanguineous families, all from the southern region of Saudi Arabia. We used linkage, homozygosity mapping and whole exome sequencing to identify the disease associated gene and mutation. Results. Linkage analysis localized sJIA to a region on chromosome 13 with a maximal LOD score of 11.33 representing the strongest linkage to date for this disorder. Homozygosity mapping reduced the critical interval to a 1.02 Mb region defined proximally by rs9533338 and distally by rs9595049. Whole exome sequencing identified a homoallelic missense mutation in LACC1 encoding the enzyme laccase (multicopper oxidoreductase) domain containing 1. The mutation was confirmed by Sanger sequencing and segregated with disease in all 5 families based upon an autosomal recessive pattern of inheritance and complete penetrance. Conclusion. Our findings provide strong genetic evidence associating mutation of LACC1 with sJIA in the families studied. Association of LACC1 with Crohn's disease and leprosy has been reported and justifies investigation of its role in autoinflammatory disorders. © 2014 American College of Rheumatology.