Discussion
The candidate region defined in the presented family overlaps with the GINGF3 interval originally defined in one Chinese family [6]. Under the hypothesis that this locus contains a single HGF gene, we refined it to a 6.56-cM, 8.28-Mb interval flanked by maker loci D2S2221 and D2S352 (Figs. 1, 4) and confirm the presence of an additional HGF gene on chromosome 2p distinct from the GINGF1 locus. The data of at least five published smaller adHGF families are compatible with linkage to this locus [5, 6]. These previous reports and our data suggest that GINGF3 is a major adHGF locus.
Previous studies on HGF suggest a function of the GINGF3 gene product in cell cycle control, and more specifically, the gene product might directly or indirectly interact with SOS1. A heterozygous SOS1 single base insertion leading to a C-terminally truncated protein, leading to sustained activation of RAS/MAPK signaling in fibroblasts, was identified in the form of HGF [12, 13]. Mutations in another component of the RAS/MAPK pathway, HRAS, can cause Costello syndrome, a malformation-dysmorphism syndrome with gingival hypertrophy as a feature [14]. Most recently, dysregulation of the human mitogen-activated protein kinase kinase 6 (MAP2K6) was implicated in the pathogenesis of a syndromic form of HGF, congenital generalized hypertrichosis terminalis [15]. Therefore, genes from the candidate region encoding for components of the RAS/MAPK pathway will be given priority regarding sequence analysis to identify the mutation causing HGF in the presented family. For example, RAB10 from the interval encodes a member of the RAS (see HRAS; OMIM 190020) superfamily of small GTPases. RAB proteins localize to exocytic and endocytic compartments and regulate intracellular vesicle trafficking; however, the particular function of RAB10 is unknown. Most genes from the candidate region are incompletely characterized such as GPN1, which encodes a guanosine triphosphatase enzyme that may play a role in DNA repair and may function in activation of transcription, and AGBL5, a putative ATP/GTP binding protein. CIB4, encoding calcium and integrin binding family member 4, may represent a further HGF candidate gene considering that calcium channel blockers can induce gingival hyperplasia. Candidates further include PPP1CB, encoding one of the three catalytic subunits of protein phosphatase 1, which is known to be involved in the regulation of cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription, and the protein encoded by FKBP1B, a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. FKBP1B is a cis-trans prolyl isomerase that binds the immunosuppressant FK506 (Tacrolimus), which can induce gingival overgrowth as a side-effect in treated patients [16, 17].
There are clinical and histological differences in the presented family as compared with SOS1-related gingival fibromatosis, which might reflect the different molecular causes of the disease. As frequently seen in HGF, an overall cell poor increase in gingival tissue with scarce blood vessels and islets with dense fibroblasts comparable to the findings in the Chinese family originally defining the GINGF3 locus [6] was noted in our patients contrasting with SOS1-related gingival fibromatosis, which features a higher increase in the number of fibroblasts compared with the increase in extracellular matrix [18]. The family presented here is also remarkable in that all patients consistently had an early onset of the disease, at the time of eruption of the primary teeth, also similar to the original Chinese GINGF3 family [6], together arguing for a clinically recognizable subtype of adHGF linked to GINGF3.
Identification of the genetic mutations involved in HGF would provide novel aids for disease diagnosis, uncover targets for novel treatment modalities, and improve our understanding of the molecular mechanisms underlying HGF and other fibrotic processes.