Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis

查看全文 作　　者：Jianfan [1,2]Chen;Xueqing [3]Xu;Song [1]Chen;Ting [4]Lu;Yingchun [1]Zheng;Zhongzhi [1]Gan;Zongrui [1]Shen;Shunfei [1]Ma;Duocai [1]Wang;Leyi [1]Su;Fei [1]He;Xuan [1]Shang;Huiyong [4]Xu;Dong [5]Chen;Leitao [4]Zhang;Fu [1,6,7]Xiong

机构地区：[1]Department of Medical Genetics,Experimental Education/Administration Center,School of Basic Medical Sciences,Southern Medical University,Guangzhou,China;[2]Experimental Department of Obstetrics and Gynecology Institute,The Third Affiliated Hospital of Guangzhou Medical University,Guangzhou,China;[3]Department of Precision Medicine,Shenzhen Hospital,Southern Medical University,Shenzhen,China;[4]Department of Stomatology,Nanfang Hospital,Southern Medical University,Guangzhou,China;[5]Department of Stomatology,The First Affiliated Hospital of Zhengzhou University,Zhengzhou,China;[6]Guangdong Provincial Key Laboratory of Single Cell Technology and Application,Guangzhou,China;[7]Department of Fetal Medicine and Prenatal Diagnosis,Zhujiang Hospital,Southern Medical University,Guangzhou,China

出　　处：《International Journal of Oral Science》索引2023年第15卷第3期,共13页

基　　金：supported by National Natural Science Foundation of China(82302078,32170617,31970558,82170920);National Key R&D Program of China(2021YFC1005301,2022YFC2703303);Natural Science Foundation of Guangdong Province of China(2022A1515012621);Grant for joint research projects from Shenzhen Hospital,Southern Medical University(22H3AUN04). 摘　　要：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 diseasecausing 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. 关键词：GINGIVAL KIF HEREDITARY

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Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis

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