A novel gene ZNF862 causes hereditary gingival fibromatosis.

Hui Huang,Juan Wu,Dongna Chen,Yanyan Wang,Junjie Zhao,Tian Zhao,Huishuang Chen,Teng Zhai,Yang Ren,Weibin Sun,Houxuan Li,Siyuan Huang,Wei Li,Ning Luo

doi:10.7554/elife.66646

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.

Highlights

Gingival fibromatosis (GF) is a rare disorder which is characterized by a benign, nonhemorrhagic, localized or generalized fibrous enlargement of free and attached gingivae with slow progression
GF could be complicated by epilepsy, hypertrichosis, and mental retardation[1,2] or it can develop as a part of syndromes like Cowden's syndrome,[3] Zimmerman-Laband syndrome,[4] Cross syndrome,[5] Rutherford syndrome,[6]
Ramon syndrome,[7] Jones syndrome,[8] Costello syndrome,[9] Ectro-amelia syndrome,[10] and hyaline fibromatosis syndrome;[11] it may be caused by poor oral hygiene related gingival inflammation, puberty, pregnancy or a side effect of the common medications such as calcium channel blockers;[12] usually it betrays as an isolated condition as non-syndromic hereditary gingival fibromatosis (HGF).[13]

Summary

Introduction

Gingival fibromatosis (GF) is a rare disorder which is characterized by a benign, nonhemorrhagic, localized or generalized fibrous enlargement of free and attached gingivae with slow progression. Whole-exome sequencing (WES) was performed for the proband and nine other members (numbers indicated in red color in Figure 1A) in the family according to previously described protocols.[26] After analyzing all single nucleotide variants (SNVs) and indels for each gene including the promoter region, exons, splicing sites, introns, and untranslated region (UTR), only three variants ATP7B (c.3403G>A), CDADC1 (c.83-13G>T), ZNF862 (c.2812G>A) were identified to be co-segregated with the phenotype among the ten family members who underwent WES.

Results

Conclusion