2. Academic Validation
  3. Germline Mutation of PLCD1 Contributes to Human Multiple Pilomatricomas through Protein Kinase D/Extracellular Signal-Regulated Kinase1/2 Cascade and TRPV6

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

  • J Invest Dermatol. 2021 Mar;141(3):533-544. doi: 10.1016/j.jid.2020.05.121.
Kai Liu 1,  Junyu Luo 2,  Tingbin Ma 1,  Muping Fang 3,  Zhe Xu 4,  Li Wang 1,  Xiang Yang Zhang 1,  Jingmin Wen 1,  Chunjie Liu 1,  Yanjie Cao 1,  Xiunan Li 1,  Luoying Zhang 1,  Anyuan Guo 1,  Ning Wang 5,  Ping Yi 1,  Jing Yu Liu 6
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China.
  • 2 Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China; Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China.
  • 3 Department of Dermatology, Xiaogan Hospital Affiliated of Wuhan University of Science and Technology, Xiaogan, China.
  • 4 Department of Dermatology, Shunyi Maternal and Children's Hospital of Beijing Children's Hospital, Beijing, China; Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
  • 5 Department of Mechanical Science and Engineering, The Grainger College of Engineering, University of Illinois, Urbana-Champaign, Urbana, Illinois, USA.
  • 6 Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. Electronic address: liujy@ion.ac.cn.
PMID: 32795530 DOI: 10.1016/j.jid.2020.05.121
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 pilomatricomas commonly have somatic mutations in the gene CTNNB1, but causative genes from germline and the underlying pathophysiology are unclear. In this study, we identified a germline missense variant of PLCD1 encoding 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 protein kinase C/protein kinase D/extracellular signal-regulated kinase1/2 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.

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