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

Raquel Rabionet, Agustín Remesal, Anna Mensa-Vilaró, Sara Murías, Rosa Alcobendas, Eva González-Roca, Estibaliz Ruiz-Ortiz, Jordi Antón, Estibaliz Iglesias, Consuelo Modesto, David Comas, Anna Puig, Oliver Drechsel, Stephan Ossowski, Jordi Yagüe, Rosa Merino, Xavier P. Estivill, Juan I. Arostegui

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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.

Original languageEnglish
Article number4579
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

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Rabionet, R., Remesal, A., Mensa-Vilaró, A., Murías, S., Alcobendas, R., González-Roca, E., Ruiz-Ortiz, E., Antón, J., Iglesias, E., Modesto, C., Comas, D., Puig, A., Drechsel, O., Ossowski, S., Yagüe, J., Merino, R., Estivill, X. P., & Arostegui, J. I. (2019). Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis. Scientific reports, 9(1), [4579]. https://doi.org/10.1038/s41598-019-40874-2