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Objective: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease, assumed to occur due to a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. Here, our objective was to identify the cause of an autosomal recessive form of SLE. Methods: We investigated three siblings from one consanguineous kindred with juvenile-onset SLE and used next generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunological and functional assays to assess the impact of the identified mutations on B cell biology. Results: We identified a homozygous missense mutation in PRKCD, encoding protein kinase delta (PKC?) in all three affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKC?, involved in the deletion of autoreactive B cells, leading to a resistance to BCR- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKC?, which exhibit an SLE phenotype and B cell expansion, we observed an increase of immature B cells in affected patients, and a developmental shift toward an immature phenotype of na�ve B cells. Conclusion: Our findings indicate that PKC? is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKC? deficiency represents a novel genetic defect of apoptosis leading to SLE. � 2013 American College of Rheumatology.