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

IF 2.9 3区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE

Oral diseases Pub Date : 2025-06-18 DOI:10.1111/odi.70000

Shi Yu, Yuanyuan Wang, Xiaojing Yuan, Yi Yang, Xin Wang, Man Qin

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引用次数: 0

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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一种新的COL12A1突变通过调节牙龈成纤维细胞功能导致口腔组织异常。

目的：本研究旨在鉴定以牙龈增生和骨骼异常为表现的乌尔里希先天性肌营养不良-2 （UCMD2）患者的一种新的COL12A1突变，并表征其对牙龈成纤维细胞（GFs）行为的功能影响。方法：全外显子组测序鉴定了一个近亲家族的COL12A1突变。从患者和健康对照中分离的GFs进行功能测定，以评估增殖、凋亡和成骨分化。GFs中慢病毒COL12A1敲低证实了表型变化。RNA测序揭示了改变的分子途径。结果：COL12A1纯合子移码突变（NM_004370: c.6747del, p.Thr2249Thrfs*44）导致XII胶原缺乏。患者源性GFs表现为过度增殖（细胞周期蛋白D1/PCNA升高，s期积累），细胞凋亡减少（Bcl2/Bax比值升高），成骨分化受损(RUNX2、OCN、OPN下调；减少矿化)。COL12A1的敲低重现了这些缺陷。转录组学显示，col12a1缺失的GFs中，干扰素- α / β反应和凋亡信号通路上调，细胞外基质（ECM）组织、细胞粘附和骨骼发育基因下调。结论：COL12A1缺乏可导致成纤维细胞过度增殖，抑制成纤维细胞凋亡，并通过失调的ECM重塑抑制成骨分化，从而破坏牙龈稳态。这些发现证实了胶原XII是神经嵴源性口腔结缔组织的关键调节因子，为col12a1相关疾病的牙龈增生和骨骼异常提供了机制见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oral diseases 医学-牙科与口腔外科

CiteScore

7.60

自引率

5.30%

发文量

325

审稿时长

4-8 weeks

期刊介绍： Oral Diseases is a multidisciplinary and international journal with a focus on head and neck disorders, edited by leaders in the field, Professor Giovanni Lodi (Editor-in-Chief, Milan, Italy), Professor Stefano Petti (Deputy Editor, Rome, Italy) and Associate Professor Gulshan Sunavala-Dossabhoy (Deputy Editor, Shreveport, LA, USA). The journal is pre-eminent in oral medicine. Oral Diseases specifically strives to link often-isolated areas of dentistry and medicine through broad-based scholarship that includes well-designed and controlled clinical research, analytical epidemiology, and the translation of basic science in pre-clinical studies. The journal typically publishes articles relevant to many related medical specialties including especially dermatology, gastroenterology, hematology, immunology, infectious diseases, neuropsychiatry, oncology and otolaryngology. The essential requirement is that all submitted research is hypothesis-driven, with significant positive and negative results both welcomed. Equal publication emphasis is placed on etiology, pathogenesis, diagnosis, prevention and treatment.