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

Area of Science:

• Genetics and Molecular Biology
• Cell Biology
• Developmental Biology

Background:

• Ullrich congenital muscular dystrophy-2 (UCMD2) is a rare genetic disorder.
• Gingival hyperplasia and skeletal anomalies are key clinical features.
• The role of COL12A1 in oral connective tissues is not well understood.

Purpose of the Study:

• Identify a novel COL12A1 mutation in a patient with UCMD2.
• Characterize the functional impact of this mutation on gingival fibroblasts (GFs).
• Elucidate the molecular mechanisms underlying gingival hyperplasia and skeletal anomalies.

Main Methods:

• Whole-exome sequencing to identify COL12A1 mutations.
• Functional assays on patient-derived GFs (proliferation, apoptosis, osteogenic differentiation).
• Lentiviral COL12A1 knockdown and RNA sequencing for mechanistic insights.

Main Results:

• A homozygous COL12A1 frameshift mutation (c.6747del) identified, causing collagen XII deficiency.
• COL12A1-deficient GFs showed hyperproliferation, reduced apoptosis, and impaired osteogenic differentiation.
• Transcriptomics revealed dysregulated interferon response, ECM organization, and skeletal development pathways.

Conclusions:

• COL12A1 deficiency disrupts gingival homeostasis, impacting fibroblast behavior and ECM remodeling.
• Collagen XII is a critical regulator of neural crest-derived oral connective tissues.
• Mechanistic insights into gingival hyperplasia and skeletal anomalies in COL12A1-related disorders are provided.