REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

Abstract

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exontruncating mutations in REST for organismal development and the association with the HGF phenotype.

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1

“…The more moderate phenotype, classical MFS, is caused by nonsense mutations that activate the NMD RNA surveillance pathway, thereby degrading mutant transcripts and resulting in FBN1 haploinsufficiency. The data support the concept of distinct pathogenetic mechanisms, GoF versus LoF (BAYRAM et al . 2017; COBAN-AKDEMIR et al .…”

“…PTCs located in the final coding exon are specifically prone to escape NMD and so are processed distinctly from those in internal exons in terms of transcript degradation, leading to the stable translation of truncated proteins (BAYRAM et al . 2017).…”

Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness

“…Although mutations in the constitutively spliced exons of REST have been linked to cancer and gingival fibromatosis (Mahamdallie et al, 2015; Bayram et al, 2017), ours is the first study to associate REST with hearing loss, and DFNA27 is the first genetic variant shown to affect the alternative splicing of REST. The effects of the DFNA27 variant are highly unusual in that either gain or loss of function of the encoded protein occurs depending on the cellular context.…”

Exomic and transcriptomic alterations of hereditary gingival fibromatosis

“…To unravel the genetic basis of HGF, past studies have mainly used linkage analysis, candidate gene approaches, and whole‐exome sequencing. As a result, chromosomes 2p21‐p22 ( GINGF ), 2p13‐p16, 2p22.3‐23 ( GINGF3 ), 5q13‐q22 ( GINGF2 ), 4q21, 4q, son of sevenless gene ( SOS1 ), and RE1‐silencing transcription factor ( REST ) have been associated with non‐syndromic HGF (Bayram, White, & Elcioglu, ; DeAngelo, Murphy, Claman, Kalmar, & Leblebicioglu, ; Sah, Chandra, & Kaur, ). However, these genetic methods have not fully revealed the mechanisms underlying idiopathic HGF.…”