Objectives Our objective was to identify the cause of an autosomalrecessive form of SLE in an inbred family with threeaffected siblings.MethodsWe investigated three siblings and used next generationsequencing to identify mutations in the disease-associatedgene. We performed extensive biochemical, immunologi-cal and functional assays to assess the impact of the identi-fied mutations on B cell biology.ResultsGenetic mapping and targeted exome sequencing lead tothe identification of a homozygous mutation in PRKCD,encoding protein kinase C delta (PKCδ). Mutation ofPRKCD resulted in reduced expression and activity ofencoded protein PKCδ.Inmouse,PKCδplays a crucialrole in the deletion of autoreactive B cells. As for micedeficient in PKCδ, we demonstrated that B cells display aresistance to calcium-dependent apoptosis and a higherproliferation rate associated with an increase of immatureB cells in affected patients, and a developmental shifttoward an immature phenotype of naïve B cells. Conclusion Our findings indicate that PKCδis crucial in regulating B cell tolerance and preventing self-reactivity in humans.