The PRKCE gene encodes protein kinase C-epsilon, a member of a large protein kinase family of enzymes that activate important proteins and are involved in cellular functions as for example growth, differentiation and apoptosis. Somatic mutations of PRKCE have been described in tumors.

Using whole-exome sequencing, researchers have now for the first time identified a de novo PRKCE mutation as the disease-causing genetic variant in a patient with SHORT syndrome. This is a very rare malformation syndrome manifesting mainly as a combination of short stature, lipoatrophy, and characteristic facial features (triangular face, broad forehead, deep-set eyes, low-hanging columella, small chin). To date, autosomal dominant mutations of the PIK3R1 gene have been the only known genetic cause of SHORT syndrome, resulting in a dysregulation of the PI3K-AKT-mTOR signaling pathway. In their functional investigations of the newly identified PRKCE mutation, the scientists showed that it leads to a partial loss of function of the encoded protein kinase C-epsilon and affects AKT activation via compromised mTORC2 complex function. This novel genetic defect in SHORT syndrome thus triggers a mechanism that, similarly to the known disease-causing PIK3R1 mutations, impairs AKT-mTOR activation.

The results of this study have been published in Human Molecular Genetics.