KCNK4 c.730G>C/p.Ala244Pro Promotes Gingival Fibroblast Proliferation and Fibrosis Through MAPK/ERK1/2 Activation in...

KCNK4-associated gingival fibromatosis (K-GF) is a rare condition characterised by progressive gingival enlargement and excessive connective tissue accumulation. Although pathogenic variants in KCNK4 have been linked to syndromic gingival overgrowth, the cellular and molecular mechanisms underlying the gingival phenotype remain incompletely understood. This study aimed to investigate the biological effects of a rare heterozygous KCNK4 c.730G>C variant identified in a paediatric patient with K-GF and to explore its potential role in gingival fibroblast dysfunction.

We employed primary fibroblasts, engineered mutant cell lines and animal models to investigate the KCNK4 mutation. The role of the ERK1/2 pathway was assessed using the inhibitor SCH 772984 and activator Ro 67-7476. Phenotypic effects on proliferation, apoptosis and fibrosis were evaluated via CCK-8, EdU, Annexin V-FITC, qPCR, Western blot, immunofluorescence, HE and Masson staining.

The KCNK4 c.730G>C mutation was associated with increased proliferative and fibrotic activity and reduced apoptotic capacity in gingival fibroblasts. Similar phenotypic changes were observed in engineered mutant cell models and, to a lesser extent, in the mouse model. Transcriptomic analysis and validation experiments indicated activation of the MAPK/ERK1/2 pathway. Pharmacological modulation further suggested that ERK1/2 signalling contributes to the proliferative imbalance of mutant gingival fibroblasts.

These findings suggest that the KCNK4 c.730G>C mutation may contribute to gingival fibromatosis by promoting gingival fibroblast proliferation and fibrosis, at least in part through MAPK/ERK1/2 pathway activation. This study provides mechanistic insight into K-GF and supports further investigation of ERK1/2-related signalling as a potential therapeutic direction.

This study highlights a possible molecular mechanism underlying KCNK4-associated gingival overgrowth and suggests that pathway-based approaches may complement surgical management in future studies. However, further validation in additional patients and preclinical models is required before clinical translation.