New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes

Abstract

Background Hereditary gingival fibromatosis (HGF) is an uncommon genetic condition characterized by slow but progressive fibrous, non‐hemorrhagic, and painless growth of the gingival tissues due to the increased deposition of collagen and other macromolecules of the extracellular matrix. HGF occurs in approximately 1:750,000 individuals and can exhibit dominant or recessive inheritance. To date, five loci (2p21‐p22, 2p22.3‐p23.3, 4q12, 5q13‐q22, and 11p15) and three genes [REST (RE1‐silencing transcription factor), SOS1 (Son‐of‐Sevenless‐1), and ZNF862 (zinc finger protein 862 gene)] have been associated with HGF. Here, our study aimed to identify genetic variants associated with HGF by applying whole‐exome sequencing (WES) and bioinformatics analyses. Methods Thirteen Brazilian individuals with HGF and nine relatives without HGF from four unrelated families were chosen for our investigation. Blood collected from the patients and their relatives were used for WES. Five Web‐available tools, namely, CADD, PolyPhen, SIFT, Mutation Taster, and Franklin's algorithms, were used to predict protein damage. Results WES revealed pathogenic variants affecting the known HGF genes REST (c.1491_1492delAG) and SOS1 (c.3265_3266insTAAC) in two families. Additionally, potentially pathogenic variants segregating in the other two families were mapped to ALK receptor tyrosine kinase gene (ALK) (c.361C > T) and to collagen type I receptor and thrombospondin receptor gene (CD36) (c.1133G > T). Conclusion Our findings reinforce the high genetic heterogeneity of HGF, identifying new variants in HGF known genes (REST and SOS1) and ALK and CD36 as new genes that cause HGF.

Pathogenic REST variant causing Jones syndrome and a review of the literature

“…In vitro, reported gene assays demonstrated that these truncated RESTs had a partial or complete loss of repressor activity and that truncated RESTs impaired the repressive ability of the wild-type REST, suggesting a dominant negative effect [9]. Recently, Machado et al reported a novel truncating REST variant segregating with mild GF in a Brazilian family [10].…”

“…REST is expressed in the epithelium and lamina propria of normal and fibrotic gingiva [9], and it controls gingival homeostasis by supressing profibrotic genes and activating proteolytic genes [9]. It is speculated that loss-of-function REST variants cause increased production but reduced turnover of the ECM leading to GF [10].…”

“…Pathogenic variants in the repressor element 1-silencing transcription factor (REST) gene (OMIM *600571) have previously been associated with dominantly inherited SNHL [6,7], GF [8][9][10], or susceptibility to Wilms tumor [11]. Here, we describe a Finnish family with a typical Jones syndrome phenotype.…”

Pathogenic REST variant causing Jones syndrome and a review of the literature

“…The TGF-β/Smad signaling cascade and overproduction of the extracellular matrix (ECM), especially collagen type I, have been proposed to account for gingival bromatosis (15,16). REST is expressed in the epithelium and lamina propria of normal and brotic gingiva (17), and it controls gingival homeostasis by supressing pro brotic genes and activating proteolytic genes (9). It is speculated that loss-of-function REST variants cause increased production but reduced turnover of the ECM leading to gingival bromatosis (17), and ChIP-seq data supports this hypothesis (18).…”

“…REST is expressed in the epithelium and lamina propria of normal and brotic gingiva (17), and it controls gingival homeostasis by supressing pro brotic genes and activating proteolytic genes (9). It is speculated that loss-of-function REST variants cause increased production but reduced turnover of the ECM leading to gingival bromatosis (17), and ChIP-seq data supports this hypothesis (18). However, the exact pathophysiological mechanisms of how REST dysfunction leads to gingival bromatosis, are currently unknown (12).…”