Abstract

Next generation sequencing (NGS) represents a revolution in the field of molecular medicine, and offers a new approach to deciphering the pathogenesis of complex diseases. Paediatric-onset SLE (pSLE) is considered as a paradigm of early-onset autoimmunity and is a very rare and more severe disease than its adult-onset counterpart. These differences are possibly associated with a greater contribution of genetic aetiological factors.

Others and we have identified the deficiency of Protein Kinase C-delta (PKC-delta) as a new cause of monogenic autoimmunity. To date, six patients in four kindred have been reported. The phenotype is broad and ranges from lymphoproliferative disease to lupus-like autoimmunity.

In mouse, PKC-delta deficiency is associated to systemic autoimmunity and is B cell autonomous. We have shown that BCR- or Thapsigargin-dependent apoptosis is impaired in patient's B cells. PKC-delta is crucial in regulating B cell negative selection.

PKC-delta is widely expressed and mutations may impact on additional immune cells. One out of our three patients has developed late-onset papillomatosis suggestive for NK cell deficiency but the underlying mechanisms remain unclear.

As described in other apoptosis deficiencies, PKC-delta deficiency may occur in a context of somatic mutation. As part of an exome sequencing panel project on SLE-related genes, we have recently screened 130 additional patients with early-onset SLE but we did not identified any homozygous or heterozygous variants suggesting PRKCD mutations remain extremely rare in juvenile SLE.