A novel gene ZNF862 causes hereditary gingival fibromatosis

  1. Juan Wu
  2. Dongna Chen
  3. Hui Huang
  4. Ning Luo
  5. Huishuang Chen
  6. Junjie Zhao
  7. Yanyan Wang
  8. Tian Zhao
  9. Siyuan Huang
  10. Yang Ren
  11. Teng Zhai
  12. Weibin Sun
  13. Houxuan Li
  14. Wei Li

  • Curated by eLife

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    Evaluation Summary:

    This work is of clinical relevance to those interested in the etiology and pathology of hereditary gingival fibromatosis (HGF). The paper discusses two novel findings: identification of a causative role of a missense mutation in the gene encoding the zinc finger protein 862 (ZNF862) that leads to hereditary gingival fibromatosis (HGF), a rare disease characterized by overgrowth of gingivae, in an examined family, and a suggestion of the molecular consequences of that mutation that leads to the disease.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

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Abstract

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis which is featured as a localized or generalized overgrowth of gingivae. Currently two genes ( SOS1 and REST ), as well as four loci (2p22.1, 2p23.3–p22.3, 5q13–q22, and 11p15), have been identified as associated with HGF in a dominant inheritance pattern. Here, we report 13 individuals with autosomal-dominant HGF from a four-generation Chinese family. Whole-exome sequencing followed by further genetic co-segregation analysis was performed for the family members across three generations. A novel heterozygous missense mutation (c.2812G > A) in zinc finger protein 862 gene ( ZNF862 ) was identified, and it is absent among the population as per the Genome Aggregation Database. The functional study supports a biological role of ZNF862 for increasing the profibrotic factors particularly COL1A1 synthesis and hence resulting in HGF. Here, for the first time we identify the physiological role of ZNF862 for the association with the HGF.

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  1. Version published to 10.7554/elife.66646 on eLife
  2. eLife

    Evaluation Summary:

    This work is of clinical relevance to those interested in the etiology and pathology of hereditary gingival fibromatosis (HGF). The paper discusses two novel findings: identification of a causative role of a missense mutation in the gene encoding the zinc finger protein 862 (ZNF862) that leads to hereditary gingival fibromatosis (HGF), a rare disease characterized by overgrowth of gingivae, in an examined family, and a suggestion of the molecular consequences of that mutation that leads to the disease.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

  3. eLife

    Reviewer #1 (Public Review):

    In this study, using whole-exome sequencing of 10 members of a family (4 generation) suffering from hereditary gingival fibromatosis revealed ZNF862 as a genetic cause for this disease. While in the 10 tested family members also mutations in 2 other genes co-segregated with the phenotype, namely ATP7B and CDADC1, these could not be validated in other family members by conventional PCR.

    Transcriptional analysis of fibroblasts from patients and healthy controls revealed an upregulation of genes associated with fibrosis like COL1A1, TGFB1/2 and SMAD1 in HGF. Furthermore, shRNA knock-down of ZNF862 in gingival fibroblasts isolated from healthy controls lead to an up-regulation of pro-fibrotic genes including TGFB/SMAD1 as well as ACTA2 and COL1A1. These assays suggest a pathophysiological role for ZNF862 in HGF, however, a detailed mechanistic analysis remains to be done.

    The authors speculate that the top 100 up- or down-regulated genes lie downstream of ZNF862. Furthermore, pathway enrichment analysis revealed an association to several infection-related pathways. The authors conclude that this is due to an association with IL-6 signaling. However, they do not provide any evidence for this conclusion.

    Since surgery is currently the only treatment for HGF patients with a high recurrence rate due to the genetic predisposition, the identification of ZNF862 as a genetic cause for the disease is of high importance for the development of a therapy.

  4. eLife

    Reviewer #2 (Public Review):

    By WES sequencing of a four-generation HGF family and co-segregation analysis, the authors identified a novel heterozygous missense mutation (c.2812G>A) in the ZNF862 gene. At the level of functional studies, through ZNF862 knockdown experiments, the authors found that the ZNF862 gene was associated with gingival tissue fibrosis to some extent. Furthermore, by comparing transcriptomic analysis of gingival fibroblasts from HGF patients and normal subjects, this study shows genes that are aberrantly expressed at the genome-wide level and the corresponding bioinformatic analysis.

    Strengths:

    WES sequencing methods are well established, the screening process for mutated genes is rigorous and reliable, and co-segregation analysis is certainly necessary.
    On the other hand, as a relatively independent experiment from the pathogenic gene screen, transcriptomic analysis of gingival fibroblasts from HGF patients is valuable, allowing the reader to take a global perspective and analyze the genes with abnormal changes in expression in HGF gingival tissue.

    Weaknesses:

    It is unreliable to claim that ZNF862 is the causative gene of HGF just by WES sequencing and co-segregation analysis; even if ZNF862 knockdown experiments were performed, this would be of little help. It is clearly insufficient evidence to exclude the presence of the c.2812G>A variant of the ZNF862 gene in normal individuals simply by searching in the relevant databases.

  5. eLife

    Reviewer #3 (Public Review):

    Wu and colleagues addressed a knowledge gap in the genetics of hereditary gingival fibromatosis, the most common form of gingival fibromatosis. The Authors investigated the genetic causes leading to HFG in a four-generation Chinese family with high incidence of the disease among its family members and found that mutation of ZNF862 was present in all affected family members and in none of the non-affected members.

    Next, the authors investigated the transcriptional landscape of explant culture derived from two members of the family with HGF and from four control individuals, confirming the hypothesis that an increase in profibrotic genes could contribute to HGF pathology. Although the sample size of the examined cohort was small and included only two affected individuals, the relevance of the results were validated in the subsequent experiment. In this experiment authors suppressed expression of ZNF862 in cells derived from a control individual using shRNAi technology and showed that indeed this led to upregulation of profibrotic genes, mimicking changes seen in HGF patients of the family.

    Overall, we commend the clear experimental design and advancing the knowledge of the genetic origins of HGF. The study presents novel findings and interesting results despite the small sample size of the experimental cohorts. However, a few aspects of data visualization could be improved such as the graphical representation of differentially expressed genes. A couple of conclusions should be backed up by further experimental data or referencing previously published studies. These conclusions are:

    - Suggestion that top down-regulated and up-regulated genes from RNA-seq lie downstream of ZNF862 and play a role in HGF pathophysiology. This claim would have to be supported by experimental data showing that ZNF862 indeed directly regulates the expression of those genes. It is possible that these genes do not contribute to the pathology of HGF.

    - The suggestion that REST and ZNF862 may execute similar transcriptional functions requires further experimental evidence or referencing previously published data showing which genes are regulated by REST, what the overlap with ZNF862 target genes is, or experimental data of ZNF862 DNA binding sites.

    Authors should also acknowledge a previous body of work on ZNF862 in their manuscript.

  6. Version published to 10.1101/2020.04.27.20080804v1 on medRxiv