KIF3C和ZNF513的双重杂合致病突变可引起遗传性牙龈纤维瘤病。

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2023-09-26 DOI:10.1038/s41368-023-00244-1
Jianfan Chen, Xueqing Xu, Song Chen, Ting Lu, Yingchun Zheng, Zhongzhi Gan, Zongrui Shen, Shunfei Ma, Duocai Wang, Leyi Su, Fei He, Xuan Shang, Huiyong Xu, Dong Chen, Leitao Zhang, Fu Xiong
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引用次数: 0

摘要

遗传性牙龈纤维瘤病(HGF)是一种罕见的牙龈组织纤维瘤样增生的遗传性疾病,表现出巨大的遗传异质性。已经鉴定了五个与非综合征HGF相关的不同基因座;然而,在GINGF1和GINGF5两个基因座上,仅鉴定出两个诱导HGF的致病基因,即SOS1和REST。在这里,基于一个有26名成员的家族谱系,包括9名HGF患者,我们在与HGF相关的GINGF3基因座内的ZNF513(c.C748T,p.R250W)和KIF3C(c.G1229A,p.R410H)基因中鉴定了双杂合致病突变。功能研究表明,ZNF513 p.R250W和KIF3C p.R410H变体在体外和体内显著增加了ZNF513和KIF3C的表达。ZNF513是一种转录因子,与KIF3C外显子1结合,参与牙龈成纤维细胞中KIF3C表达的正调控。此外,敲除小鼠模型证实,Zfp513(p.R250W)或Kif3c(p.R412H)内的杂合或纯合突变单独不会导致牙龈纤维瘤病的明确表型,而双重突变导致牙龈增生表型。此外,我们发现ZNF513与SOS1启动子结合,并在调节SOS1的表达方面发挥重要的积极作用。此外,KIF3C p.R410H突变可以激活PI3K和KCNQ1钾通道。ZNF513与KIF3C联合通过PI3K/AKT/mTOR和Ras/Raf/MEK/ERK途径调节牙龈成纤维细胞增殖、迁移和纤维化反应。总之,这些结果证明了ZNF513 + KIF3C是HGF表现中的重要基因组合,提示ZNF513突变可能是HGF的主要危险因素。
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Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis.

Hereditary gingival fibromatosis (HGF) is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity. Five distinct loci related to non-syndromic HGF have been identified; however, only two disease-causing genes, SOS1 and REST, inducing HGF have been identified at two loci, GINGF1 and GINGF5, respectively. Here, based on a family pedigree with 26 members, including nine patients with HGF, we identified double heterozygous pathogenic mutations in the ZNF513 (c.C748T, p.R250W) and KIF3C (c.G1229A, p.R410H) genes within the GINGF3 locus related to HGF. Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo. ZNF513, a transcription factor, binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts. Furthermore, a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513 (p.R250W) or Kif3c (p.R412H) alone do not led to clear phenotypes with gingival fibromatosis, whereas the double mutations led to gingival hyperplasia phenotypes. In addition, we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1. Moreover, the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels. ZNF513 combined with KIF3C regulates gingival fibroblast proliferation, migration, and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways. In summary, these results demonstrate ZNF513 + KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.

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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
期刊最新文献
Organoids in the oral and maxillofacial region: present and future. Personalized bioceramic grafts for craniomaxillofacial bone regeneration An unexpected role of neurite outgrowth inhibitor A as regulator of tooth enamel formation Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches. CREB3L1 deficiency impairs odontoblastic differentiation and molar dentin deposition partially through the TMEM30B.
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