Germline mutation of PLCD1 contributes to human multiple pilomatricomas via PKD/ERK1/2 cascade and TRPV6

Abstract Pilomatricoma, a benign skin appendage tumor, also known as calcifying epithelioma, consists of islands of epithelial cells histologically that contain anucleated cells in the center surrounded by basophilic cells, and partial calcification. Sporadic pilomatricoms commonly have somatic mutations in the gene CTNNB1, but causative genes from germline and the underlying pathophysiology are unclear. Here, we identified a germline missense variant of PLCD1 encoding phospholipase C delta 1 (PLCδ1), c.1186G>A (p.Glu396Lys), in a large Chinese family with autosomal dominant multiple pilomatricomas. Phospholipase C, a key enzyme playing critical roles in intracellular signal transduction, is essential for epidermal barrier integrity. The p.Glu396Lys variant increased the enzymatic activity of PLCδ1, leading to PKC/PKD/ERK1/2 pathway activation and TPRV6 channel closure, which not only resulted in excessive proliferation of keratinocytes in vitro and in vivo, but also induced local accumulation of calcium in the pilomatricoma-like tumor that developed spontaneously in the skin of Plcd1E396K/E396K mice. Our results implicate this p.Glu396Lys variant of PLCD1 from germline leading to gain-of-function of PLCδ1 as a causative genetic defect in familial multiple pilomatricomas.