Chymase Deficiency Drives Non-Syndromic Hereditary Gingival Fibromatosis

Hereditary gingival fibromatosis (HGF) is an inherited disease characterized by pathological gingival overgrowth, but the mechanisms underlying HGF remain largely elusive. Whole-genome sequencing was performed to identify the pathological mutation in a Chinese family with non-syndromic HGF. The chymase levels in patients' gingival fibroblasts were quantified by Western blot. Human gingival fibroblasts were transfected with siRNA to silence CHYMASE expression. The levels of fibrosis markers and YAP/TAZ in gingival fibroblasts was quantified by qPCR and Western blot. To explore pro-fibrotic behavior of CHYMASE-silenced gingival fibroblasts in vivo, gingival fibroblasts were infected with shRNA to silence CHYMASE expression and then transplanted subcutaneously into the right axillae of NOD/SCID male mice (n=3 mice in each group). HEK 293T/17-derived exosomes loaded with verteporfin were topical administrated. Histological alterations in the right axillae were evaluated using hematoxylin & eosin and Masson staining. We for the first time identified a nonsense mutation (c.114C>A) in the CHYMASE gene that potentially caused non-syndromic HGF in a Chinese family. The CHYMASE variant decreased chymase expression in the patient's gingival fibroblasts, thus directly leading to extracellular matrix deposition via YAP/TAZ activation. In the mouse model, exosomes loaded with the YAP specific inhibitor verteporfin significantly attenuated chymase deficiency-induced tissue fibrosis. Our findings establish the contributory role of chymase deficiency in non-syndromic HGF through YAP/TAZ pathway, and additionally, shed light on the verteporfin loaded-exosomes as promising therapeutic agents for non-syndromic HGF.