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.
Animals ; Humans ; Mice ; Fibromatosis, Gingival/pathology* ; Gingiva ; Kinesins/genetics* ; Mutation/genetics* ; Phosphatidylinositol 3-Kinases/genetics*

Gingival fibromatosis is a rare disease, especially its syndromic form. Here, we review the literatures on gingival fibromatosis and briefly summarize some characters on clinical, etiological, genetic and histopathological aspects. We also present a rare case of gingival fibromatosis with multiple unusual findings in a 21-year-old man. And we differentiate it from some well-known syndromes including gingival fibromatosis. Maybe it implies a new syndrome within the spectrum of those including gingival fibromatosis.
Atrophy ; Bone Diseases, Developmental ; diagnosis ; Cataract ; congenital ; Cerebellum ; pathology ; Deafness ; diagnosis ; Diagnosis, Differential ; Fibromatosis, Gingival ; diagnosis ; Frontal Lobe ; pathology ; Gingival Overgrowth ; diagnosis ; Humans ; Male ; Maxillary Diseases ; diagnosis ; Young Adult

OBJECTIVETo ascertain histology changes of hereditary gingival fibromatosis (HGF) and the location of HGF gene.

METHODSA pedigree analyses of HGF; and the ultrastructure of gingival overgrowth tissue was observed with electron microscopy. The overgrowth of the HGF gene was defined with microsatellite markers.

RESULTSThe connective tissue of HGF consisted of coarse collagen bundles and several kinds of cells arranged abnormally, such as: epithelial cells, smooth muscle cells and so on; the HGF locus had been mapped to chromosome 5q13-q22.

CONCLUSIONSThe gingival pathologic changes resemble "hamartoma"; the findings has implications for identification of the underlying genetic basis of HGF.

Child ; Chromosome Mapping ; Chromosomes, Human, Pair 5 ; genetics ; Family Health ; Female ; Fibromatosis, Gingival ; genetics ; pathology ; ultrastructure ; Genetic Predisposition to Disease ; genetics ; Gingiva ; metabolism ; pathology ; ultrastructure ; Humans ; Male ; Microsatellite Repeats ; Microscopy, Electron ; Pedigree