A Novel COL12A1 Mutation Causes Oral Tissue Abnormalities by Regulating Gingival Fibroblast Function

This study aimed to identify a novel COL12A1 mutation in a patient with Ullrich congenital muscular dystrophy-2 (UCMD2) presenting with gingival hyperplasia and skeletal anomalies and to characterize its functional impact on gingival fibroblasts (GFs) behavior.

Whole-exome sequencing identified COL12A1 mutations in a consanguineous family. GFs isolated from the patient and healthy controls underwent functional assays to assess proliferation, apoptosis, and osteogenic differentiation. Lentiviral COL12A1 knockdown in GFs validated phenotypic changes. RNA sequencing elucidated altered molecular pathways.

A homozygous COL12A1 frameshift mutation (NM_004370: c.6747del, p.Thr2249Thrfs*44) caused collagen XII deficiency. Patient-derived GFs exhibited hyperproliferation (elevated cyclin D1/PCNA, S-phase accumulation), reduced apoptosis (increased Bcl2/Bax ratio), and impaired osteogenic differentiation (downregulated RUNX2, OCN, OPN; reduced mineralization). COL12A1 knockdown recapitulated these defects. Transcriptomics revealed upregulated interferon-alpha/beta response and apoptotic signaling pathways, alongside downregulated extracellular matrix (ECM) organization, cell adhesion, and skeletal development genes in COL12A1-deficient GFs.

COL12A1 deficiency disrupts gingival homeostasis by driving fibroblast hyperproliferation, inhibiting fibroblast apoptosis, and suppressing osteogenic differentiation via dysregulated ECM remodeling. These findings establish collagen XII as a critical regulator of neural crest-derived oral connective tissues, providing mechanistic insights into gingival hyperplasia and skeletal anomalies in COL12A1-related disorders.