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.

遗传性牙龈纤维瘤病（HGF）是一种罕见的遗传性疾病，牙龈组织纤维瘤样增生，表现出极大的遗传异质性。已鉴定出与非综合征性 HGF 相关的 5 个不同位点；然而，仅在两个基因座 GINGF1 和 GINGF5 上仅鉴定出两个诱导 HGF 的致病基因SOS1和REST 。在这里，基于一个有 26 名成员（包括 9 名 HGF 患者）的家族谱系，我们鉴定了GINGF3 内ZNF513（c.C748T，p.R250W）和KIF3C （c.G1229A，p.R410H）基因的双杂合致病性突变与 HGF 相关的位点。功能研究表明，ZNF513 p.R250W 和KIF3C p.R410H 变体在体外和体内显着增加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表达的正向调节。此外，敲入小鼠模型证实，单独的Zfp513（p.R250W）或Kif3c（p.R412H）内的杂合或纯合突变不会导致牙龈纤维瘤病的明确表型，而双突变则导致牙龈增生表型。此外，我们发现ZNF513与SOS1启动子结合，在调节SOS1的表达中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 通路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ZNF513  +  KIF3C是 HGF 表现中的重要遗传组合，并表明ZNF513突变可能是 HGF 的主要危险因素。