Identification of human PRKCD deficiency as a monogenetic B-cell deficiency associated with autoimmunity. (A) Single nucleotide polymorphism array–based homozygosity mapping was performed and revealed several homozygous candidate intervals, including an interval on chromosome 3p21.31. (B) Sanger sequencing validated a splice site mutation in PRKCD, encoding for protein kinase C δ which was homozygous in the patient. (C) Western blot analysis showed absent expression of the corresponding protein product in the patient compared with decreased expression in the heterozygous father and normal expression in a healthy control. (D) Western blot analysis showed defective phosphorylation of MARCKS, a downstream target of PRKCD. (E) Quantitative polymerase chain reaction analysis showed hyperactive NF-IL6 signaling on stimulation using phorbol myristate acetate, as indicated by increased mRNA levels of NF-IL6 and IL6.