Association of a Mutation in LACC1 With a Monogenic Form of Systemic Juvenile Idiopathic Arthritis
Open Access
- 12 September 2014
- journal article
- pediatric rheumatology
- Published by Wiley in Arthritis & Rheumatology
- Vol. 67 (1), 288-295
- https://doi.org/10.1002/art.38877
Abstract
Objective The pathologic basis of systemic juvenile idiopathic arthritis (JIA) is a subject of some controversy, with evidence for both autoimmune and autoinflammatory etiologies. Several monogenic autoinflammatory disorders have been described, but thus far, systemic JIA has only been attributed to a mutation of MEFV in rare cases and has been weakly associated with the HLA class II locus. This study was undertaken to identify the cause of an autosomal‐recessive form of systemic JIA. Methods We studied 13 patients with systemic JIA from 5 consanguineous families, all from the southern region of Saudi Arabia. We used linkage analysis, homozygosity mapping, and whole‐exome sequencing to identify the disease‐associated gene and mutation. Results Linkage analysis localized systemic JIA to a region on chromosome 13 with a maximum logarithm of odds score of 11.33, representing the strongest linkage identified 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, which encodes the enzyme laccase (multicopper oxidoreductase) domain–containing 1. The mutation was confirmed by Sanger sequencing and segregated with disease in all 5 families based on an autosomal‐recessive pattern of inheritance and complete penetrance. Conclusion Our findings provide strong genetic evidence of an association of a mutation in LACC1 with systemic JIA 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.Keywords
Funding Information
- King Faisal Specialist Hospital & Research Centre, Riyadh (2020023)
This publication has 39 references indexed in Scilit:
- Identification of IL18RAP/IL18R1 and IL12B as Leprosy Risk Genes Demonstrates Shared Pathogenesis between Inflammation and Infectious DiseasesAmerican Journal of Human Genetics, 2012
- Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritisNature Genetics, 2012
- Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47Nature Genetics, 2011
- Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsetsArthritis & Rheumatism, 2009
- Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathwaysNature Genetics, 2009
- Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's diseaseNature Genetics, 2008
- Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritisArthritis & Rheumatism, 2008
- Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-ANature, 2007
- Basic and applied features of multicopper oxidases, CueO, bilirubin oxidase, and laccaseThe Chemical Record, 2007
- A candidate gene for familial Mediterranean feverNature Genetics, 1997