2024-03-28T11:53:48Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/2078712021-12-27T16:53:53Zcom_10261_9676com_10261_8col_10261_9677
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
Arostegui, Juan Ignacio
Generalitat de Catalunya
European Commission
Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
Sociedad Española de Reumatología
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.
The authors would like to thank the CRG Genomics Unit for assistance with whole exome sequencing. This work has been partially funded by: CERCA Programme/Generalitat de Catalunya (JIA, XE, SO), the PERIS program of the Generalitat de Catalunya grant SLT002/16/00310 (RR), the Spanish Ministry of Economy and Competitiveness co-financed by European Regional Development Fund (ERDF) grant SAF2015-68472-C2-1-R (JIA), the Instituto de Salud Carlos III/Transnational Research Projects on Rare Diseases (JIA) grant AC15/00027, the Spanish Society of Pediatric Rheumatology (JIA), the Secretaria d’Universitats i Recerca del Departament d’Economia grant 2009-SGR-1502 (XE) and the European Union Seventh Framework Programme (FP7/2007-2013) grant agreement no. 262055 (XE). We also acknowledge support of the Spanish Ministry of Economy and Competitiveness (MEIC) to the EMBL partnership, ‘Centro de Excelencia Severo Ochoa’.
2020-04-16T11:04:12Z
2020-04-16T11:04:12Z
2019-03-14
2020-04-16T11:04:12Z
artículo
http://purl.org/coar/resource_type/c_6501
doi: 10.1038/s41598-019-40874-2
e-issn: 2045-2322
Scientific Reports 9: 4579 (2019)
http://hdl.handle.net/10261/207871
10.1038/s41598-019-40874-2
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100002809
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003329
30872671
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-68472-C2-1-R
Publisher's version
http://doi.org/10.1038/s41598-019-40874-2
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open
Springer Nature