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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, SOS1and 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 ZNF513p.R250W and KIF3Cp.R410H variants significantly increased the expression of ZNF513and KIF3Cin vitro and in vivo. ZNF513, a transcription factor, binds to KIF3Cexon 1 and participates in the positive regulation of KIF3Cexpression 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 SOS1promoter and plays an important positive role in regulating the expression of SOS1. Moreover, the KIF3Cp.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+ KIF3Cas an important genetic combination in HGF manifestation and suggest that ZNF513mutation may be a major risk factor for HGF.

Tooth development is a complex process that involves precise and time-dependent orchestration of multiple genetic, molecular, and cellular interactions. Ameloblastin (AMBN, also named “amelin” or “sheathlin”) is the second most abundant enamel matrix protein known to have a key role in amelogenesis. Amelogenesis imperfecta (AI [MIM: 104500]) refers to a genetically and phenotypically heterogeneous group of conditions characterized by inherited developmental enamel defects. The hereditary dentin disorders comprise a variety of autosomal-dominant genetic symptoms characterized by abnormal dentin structure affecting either the primary or both the primary and secondary teeth. The vital role of Ambnin amelogenesis has been confirmed experimentally using mouse models. Only two cases have been reported of mutations of AMBNassociated with non-syndromic human AI. However, no AMBNmissense mutations have been reported to be associated with both human AI and dentin disorders. We recruited one kindred with autosomal-dominant amelogenesis imperfecta (ADAI) and dentinogenesis imperfecta/dysplasia characterized by generalized severe enamel and dentin defects. Whole exome sequencing of the proband identified a novel heterozygous C-T point mutation at nucleotide position 1069 of the AMBNgene, causing a Pro to Ser mutation at the conserved amino acid position 357 of the protein. Exfoliated third molar teeth from the affected family members were found to have enamel and dentin of lower mineral density than control teeth, with thinner and easily fractured enamel, short and thick roots, and pulp obliteration. This study demonstrates, for the first time, that an AMBNmissense mutation causes non-syndromic human AI and dentin disorders. A mutation on a gene involved in healthy tooth development may cause both enamel and dentin disorders. The ameloblastin enamel protein, and its associated gene, AMBN, play vital roles in enamel formation and tooth remodelling. Mutations on AMBNcan cause amelogenesis imperfecta (AI), a genetic and hereditory condition resulting in enamel defects and severe tooth decay. Now, Fu Xiong and Bu-Ling Wu at Southern Medical University in Guangzhou, China, and co-workers have identified an AMBNmutation found in both enamel and dentin defect disorders. The researchers analyzed extracted teeth from a Chinese patient with both AI and a severe dentin disorder, along with teeth from affected and non-affected members of the same family, and compared the results with a control group. They identified a rare mutation on AMBNcommon to all affected individuals.