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

Research output: Contribution to journalArticle

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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Juvenile Arthritis
Rheumatoid Factor
Mutation
Genes
Exome
Chromosomes, Human, Pair 6
Chromosomes, Human, Pair 3
Joint Diseases
Rheumatic Diseases
Computational Biology
Arthritis
Siblings
Genotype

ASJC Scopus subject areas

  • General

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Rabionet, R., Remesal, A., Mensa-Vilaró, A., Murías, S., Alcobendas, R., González-Roca, E., ... 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

Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis. / Rabionet, Raquel; Remesal, Agustín; Mensa-Vilaró, Anna; Murías, Sara; Alcobendas, Rosa; González-Roca, Eva; Ruiz-Ortiz, Estibaliz; Antón, Jordi; Iglesias, Estibaliz; Modesto, Consuelo; Comas, David; Puig, Anna; Drechsel, Oliver; Ossowski, Stephan; Yagüe, Jordi; Merino, Rosa; Estivill, Xavier P.; Arostegui, Juan I.

In: Scientific reports, Vol. 9, No. 1, 4579, 01.12.2019.

Research output: Contribution to journalArticle

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, XP & Arostegui, JI 2019, 'Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis', Scientific reports, vol. 9, no. 1, 4579. https://doi.org/10.1038/s41598-019-40874-2
Rabionet, Raquel ; Remesal, Agustín ; Mensa-Vilaró, Anna ; Murías, Sara ; Alcobendas, Rosa ; González-Roca, Eva ; Ruiz-Ortiz, Estibaliz ; Antón, Jordi ; Iglesias, Estibaliz ; Modesto, Consuelo ; Comas, David ; Puig, Anna ; Drechsel, Oliver ; Ossowski, Stephan ; Yagüe, Jordi ; Merino, Rosa ; Estivill, Xavier P. ; Arostegui, Juan I. / Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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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.",
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AU - Remesal, Agustín

AU - Mensa-Vilaró, Anna

AU - Murías, Sara

AU - Alcobendas, Rosa

AU - González-Roca, Eva

AU - Ruiz-Ortiz, Estibaliz

AU - Antón, Jordi

AU - Iglesias, Estibaliz

AU - Modesto, Consuelo

AU - Comas, David

AU - Puig, Anna

AU - Drechsel, Oliver

AU - Ossowski, Stephan

AU - Yagüe, Jordi

AU - Merino, Rosa

AU - Estivill, Xavier P.

AU - Arostegui, Juan I.

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N2 - 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.

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