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Anti-nuclear antibodies are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma. However, the molecular mechanisms of B cell tolerance breakdown in these pathological contexts are poorly known. The study of rare familial forms of autoimmune diseases could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we identified a new heterozygous mutation (p.R594C) in ERN1 gene, encoding IRE1α (Inositol-Requiring Enzyme 1α), in a multiplex family with several members presenting autoantibody-mediated autoimmunity. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation led to a profound defect of IRE1α ribonuclease activity on X-Box Binding Protein 1 (XBP1) splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of spliced form of XBP1 (XBP1s) production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1α which are important to consider for the development of IRE1α targeting strategies. • We described a heterozygous ERN1 c.1780C>T (IRE1a p.R594C) in a multiplex family of autoimmune patients. • IRE1a R594C mutation leads to a profound impairment of XBP1 splicing activity of IRE1a in human cells and in mice. • R594C transgenic mice displayed a broad breakdown of B cell tolerance. • Immune cell compartments were deeply analysed with CITEseq/FlowSOM technologies and VDJ repertoire by ImmunoSEQ technology. [ABSTRACT FROM AUTHOR]