Germline Mutation of PLCD1 Contributes to Human Multiple Pilomatricomas through Protein Kinase D/Extracellular Signal–Regulated Kinase1/2 Cascade and TRPV6

Pilomatricoma, a benign skin appendage tumor, also known as calcifying epithelioma, consists of islands epithelial cells histologically that contain anucleated in the center surrounded by basophilic and partial calcification. Sporadic pilomatricomas commonly have somatic mutations gene CTNNB1, but causative genes from germline underlying pathophysiology are unclear. In this study, we identified missense variant PLCD1 encoding PLCδ1, c.1186G>A (p.Glu396Lys), large Chinese family with autosomal dominant multiple pilomatricomas. Phospholipase C, key enzyme playing critical roles intracellular signal transduction, is essential for epidermal barrier integrity. The p.Glu396Lys increased enzymatic activity leading to protein kinase C/protein D/extracellular signal–regulated kinase1/2 pathway activation TPRV6 channel closure, which not only resulted excessive proliferation keratinocytes vitro vivo induced local accumulation calcium pilomatricoma-like tumor developed spontaneously Plcd1E396K/E396K mice. Our results implicate gain-of-function PLCδ1 genetic defect familial