Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis

Abstract

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128_129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.

Figure 1

Panel (A). Family’s pedigree. Black filled symbols represent affected individuals, open symbols, unaffected individuals, squares, male individuals, and circles, female individuals. The asterisks indicate individuals evaluated by whole-exome sequencing. Panel (B). (top) Genomic organization of the LACC1/FAMIN gene and (bottom) Sanger sense chromatograms from a homozygous wild-type healthy control (left box), heterozygous individuals (middle box), and homozygous mutated patients (right box). The asterisks indicate the two deleted nucleotide positions detected in the patients. Panel (C). (top) Normal structure of laccase protein, and (bottom) predicted structure of the truncated protein encoded by the mutated p.Cys43Tyrfs*6 LACC1/FAMIN allele.