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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.

Aim To describe a spectrum of intracerebral large artery disease in Aicardi–Goutieres syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1.