FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2731570147> ?p ?o ?g. }

• W2731570147 endingPage "156" @default.
• W2731570147 startingPage "149" @default.
• W2731570147 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-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype. 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-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype. Gingival fibromatosis (GF) is a rare condition of gingival overgrowth characterized by a slowly progressive, benign, localized or generalized fibrous enlargement of maxillary and mandibular keratinized gingiva. GF may co-exist with various genetic syndromes (i.e., generalized hypertrichosis terminalis [MIM: 135400], Zimmermann-Laband syndrome [MIM: 135500], amelogenesis imperfecta type IG [MIM: 204690], hyaline fibromatosis syndrome [MIM: 228600], etc.) or occurs as an apparent isolated trait as non-syndromic hereditary gingival fibromatosis (HGF).1Gawron K. Łazarz-Bartyzel K. Potempa J. Chomyszyn-Gajewska M. Gingival fibromatosis: clinical, molecular and therapeutic issues.Orphanet J. Rare Dis. 2016; 11: 9Crossref PubMed Scopus (52) Google Scholar GF may also develop from environmental exposure such as a side effect of medications including anticonvulsants (i.e., phenytoin), immunosuppressants (i.e., cyclosporine), or calcium channel blockers (i.e., nifedipine, diltiazem, and verapamil).2Kataoka M. Kido J. Shinohara Y. Nagata T. Drug-induced gingival overgrowth--a review.Biol. Pharm. Bull. 2005; 28: 1817-1821Crossref PubMed Scopus (81) Google Scholar, 3Trackman P.C. Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth.J. Dent. Res. 2015; 94: 540-546Crossref PubMed Scopus (83) Google Scholar The initial differential diagnosis for GF also includes chronic hyperplastic gingivitis, leukemic infiltrate, and some systemic diseases such as Crohn disease (MIM: 266600), neurofibromatosis (MIM: 162200), primary amyloidosis (MIM: 204850), sarcoidosis (MIM: 181000), scurvy (MIM: 240400), and Wegener granulomatosis (MIM: 608710) that have been associated with gingival overgrowth.4Khera P. Zirwas M.J. English 3rd, J.C. Diffuse gingival enlargement.J. Am. Acad. Dermatol. 2005; 52: 491-499Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar HGF is the most common genetic form of GF which is usually transmitted as an autosomal-dominant trait. Simplex cases are also common and autosomal-recessive inheritance has been reported.5Takagi M. Yamamoto H. Mega H. Hsieh K.J. Shioda S. Enomoto S. Heterogeneity in the gingival fibromatoses.Cancer. 1991; 68: 2202-2212Crossref PubMed Scopus (53) Google Scholar, 6Majumder P. Nair V. Mukherjee M. Ghosh S. Dey S.K. The autosomal recessive inheritance of hereditary gingival fibromatosis.Case Rep. Dent. 2013; 2013: 432864PubMed Google Scholar To date, four loci (2p22.1 [MIM: 135300], 5q13–q22 [MIM: 605544], 2p23.3–p22.3 [MIM: 609955], and 11p15 [MIM: 611010]) have been associated with HGF; a heterozygous frameshift mutation in SOS1 (MIM: 182530) has been reported as the cause of autosomal-dominant HGF in a family showing linkage to 2p21.7Hart T.C. Zhang Y. Gorry M.C. Hart P.S. Cooper M. Marazita M.L. Marks J.M. Cortelli J.R. Pallos D. A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1.Am. J. Hum. Genet. 2002; 70: 943-954Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar The estimated frequency of HGF is 1:175,000, equally affecting males and females.1Gawron K. Łazarz-Bartyzel K. Potempa J. Chomyszyn-Gajewska M. Gingival fibromatosis: clinical, molecular and therapeutic issues.Orphanet J. Rare Dis. 2016; 11: 9Crossref PubMed Scopus (52) Google Scholar The surgical treatment, gingivectomy with gingivoplasty, can be applied to individuals with massive gingival enlargement in cases of aesthetic concern; nevertheless, the recurrence of hyperplasia is relatively high potentially because of the genetic predisposition especially in hereditary forms. We report three unrelated families with eleven affected individuals clinically diagnosed with GF. Genomic analysis of these families led to the identification of three different heterozygous mutations predicted by conceptual translation to result in premature termination of the nascent transcript, two frameshifts, and one nonsense allele, in the RE1-silencing transcription factor gene (REST). Two affected siblings (II-1 and II-2 in Figure 1A) and their mildly affected father (I-1 in Figure 1A) from family 1 were referred to Marmara University School of Medicine, and six affected individuals (II-2, II-5, II-6, III-1, III-3, and III-5 in Figure 1B) from family 2 were referred to Istanbul Faculty of Medicine, in Turkey. Intraoral examination revealed severe generalized GF in all affected individuals in both families except the father (BAB4124, I-1 in Figure 1A) in family 1. His clinical examination revealed mild gingival overgrowth while both of his affected sons (BAB4122, II-1 and BAB4125, II-2 in Figure 1A) had more severe GF. The deceased maternal grandfather in family 2 (I-1 in Figure 1B) was also reported to have similar signs of gingival enlargement. Exposure to any medication that may cause GF was excluded in all individuals. Genetic analysis including karyotype and SOS1 mutation screening on the proband in family 2 prior to whole-exome sequencing (WES) revealed normal results. The clinical findings of affected individuals with available data are summarized in Table 1; detailed case reports can be found in the Supplemental Note and photos are available in Figure 1. Additionally, a case report of family 2 including clinical findings, karyotype, and SOS1 mutation analysis results was previously published by Pehlivan et al.8Pehlivan D. Abe S. Ozturk S. Kayhan K.B. Gunduz E. Cefle K. Bayrak A. Ark N. Gunduz M. Palanduz S. Cytogenetic analysis and examination of SOS1 gene mutation in a Turkish family with hereditary gingival fibromatosis.J. Hard Tissue Biol. 2009; 18: 131-134Crossref Scopus (4) Google ScholarTable 1Clinical Summary of the Individuals with REST VariantsFamily 1Family 2Family 3BAB4122BAB4124BAB4125BAB4235BAB4236BAB4237BAB4238BAB4239ProbandIdentified variantp.Asn958Serfs∗9p.Asn958Serfs∗9 (mosaic)p.Asn958Serfs∗9p.Leu437∗p.Leu437∗p.Leu437∗p.Leu437∗p.Leu437∗p.Leu805Phefs∗38Age at last exam17 years48 years13 years9 years38 years14 years16 years32 years9 yearsGendermalemalemalemalefemalefemalemalemalefemaleGingival fibromatosis++ (mild)+++++++Age of onset7–8 yearsNA7–8 years3–4 years3–4 years3–4 years3–4 years3–4 years3–4 yearsExposure to medicationnononononononononoGingivectomy/recurrence+/NANA/NA+/NANA/NANA/NANA/NANA/NANA/NA+/+Pectus deformity+no+nonononono+Other clinical findingsosteomyelitis, osteoporosisNANANANANANANAsmall hiatal hernia, short stature, recurrent URIsAbbreviations are as follows: NA, not available; URIs, upper respiratory infections Open table in a new tab Abbreviations are as follows: NA, not available; URIs, upper respiratory infections After informed consent was obtained from all participants according to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) research protocol (IRB protocol number: H-29697), WES was performed on probands (BAB4122, II-1 in Figure 1A and BAB4235, III-5 in Figure 1B) in families 1 and 2 according to previously described protocols.9Lupski J.R. Gonzaga-Jauregui C. Yang Y. Bainbridge M.N. Jhangiani S. Buhay C.J. Kovar C.L. Wang M. Hawes A.C. Reid J.G. et al.Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy.Genome Med. 2013; 5: 57Crossref PubMed Scopus (80) Google Scholar In brief, genomic DNA samples underwent whole-exome capture using VCRome 2.1 design10Bainbridge M.N. Wang M. Wu Y. Newsham I. Muzny D.M. Jefferies J.L. Albert T.J. Burgess D.L. Gibbs R.A. Targeted enrichment beyond the consensus coding DNA sequence exome reveals exons with higher variant densities.Genome Biol. 2011; 12: R68Crossref PubMed Scopus (155) Google Scholar (42 Mb NimbleGen, Cat. No. 06266380001) according to the manufacturer’s protocol (NimbleGen SeqCap EZ Exome Library SR User’s Guide) with minor modifications, followed by sequencing on the HiSeq platform (Illumina) with a sequencing yield of 8.4 Gb; the samples achieved 96% of the targeted exome bases covered to a depth-of-coverage of 20× or greater.11Challis D. Yu J. Evani U.S. Jackson A.R. Paithankar S. Coarfa C. Milosavljevic A. Gibbs R.A. Yu F. An integrative variant analysis suite for whole exome next-generation sequencing data.BMC Bioinformatics. 2012; 13: 8Crossref PubMed Scopus (198) Google Scholar Data produced were aligned and mapped to the human genome reference sequence (hg19) using the Mercury in-house bioinformatics pipeline.12Reid J.G. Carroll A. Veeraraghavan N. Dahdouli M. Sundquist A. English A. Bainbridge M. White S. Salerno W. Buhay C. et al.Launching genomics into the cloud: deployment of Mercury, a next generation sequence analysis pipeline.BMC Bioinformatics. 2014; 15: 30Crossref PubMed Scopus (159) Google Scholar Variants were called using the ATLAS variant calling method and the Sequence Alignment/Map (SAMtools) suites and annotated with an in-house-developed Cassandra annotation pipeline that uses Annotation of Genetic Variants (ANNOVAR) and additional tools and databases. Then, we applied variant prioritization for indels as the following. If an indel is reported as a variant in the Human Gene Mutation Database (HGMD) and its frequency is less than 5% in the 1000 Genomes Project (1000GP) data, it was included. If it is not present in HGMD, it has to pass through all of the variant quality filters and its frequency has to be less than 2% in 1000GP data to be prioritized and investigated further as a potential pathogenic variant. In a second filtering step, another filter is further applied based on the number of samples having the variant in Atherosclerosis Risk in Communities Study (ARIC) database. The number of samples having the variant in the ARIC database should be less than 120 out of 10,940 samples in total. For single nucleotide variants (SNVs), we applied different filtering criteria. If a SNV is reported as a variant in the HGMD or it has a clinical variant value between 3 and 8 in the Single Nucleotide Polymorphism database (dbSNP), its frequency has to be less than 5% in both 1000GP data and NHLBI GO Exome Sequencing Project (ESP5400) African and European populations. If it is not present in HGMD and does not have a clinical variant value between 3 and 8 in dbSNP, it has to pass through all of the variant quality filters and its frequency has to be less than 1% in both 1000GP data and ESP5400 African and European populations to be prioritized and investigated further as a potential pathogenic variant. Like indels, the SNVs that pass these filters were further filtered based on the number of samples having the variant in the ARIC database (should be less than 120 out of 10,940 samples in total). At the end of those filtering steps for SNVs and indels, we obtained ∼800 variants on average for each sample. Given the apparent autosomal-dominant inheritance pattern in the pedigrees of families 1 and 2, we focused on the heterozygous variants in the parsed and filtered WES data. Out of ∼800 variants, we selected the heterozygous variants that have an allele frequency below 0.1% in our internal database (CMG), which consists of more than 6,500 exomes including ∼1,050 Turkish exomes. Then potential pathogenic variants including indels, nonsense and splice site variants, and missense variants that were predicted as deleterious in at least three out of five computational algorithms including SIFT, PolyPhen-2, LRT, MutationTaster, and PROVEAN were selected as candidate variants. After these filtering steps, ∼50 heterozygous candidate variants remained for manual inspection from the personal genome analysis for each individual. The comparative analysis of the filtered WES variants revealed that deleterious mutations in REST were shared in the unrelated individuals. We identified two different heterozygous truncating variants in REST including a frameshift deletion in subject BAB4122 (family 1, II-1 in Figure 1A) (GenBank: NM_005612.4; exon 4; c.2865_2866delAA [p.Asn958Serfs∗9]; chr4:57,797,888_CAA>C; variant to total reads = 5/19) and a nonsense variant in subject BAB4235 (family 2, III-5 in Figure 1B) (GenBank: NM_005612.4; exon 4; c.1310T>A [p.Leu437∗]; chr4:57,796,334_T>A; variant to total reads = 18/33). Additionally, after those above-mentioned filtering steps, we extracted all frameshift and stopgain variants in our CMG database and developed a computational workflow to predict whether they are likely to be subject to nonsense-mediated decay (NMD-competent) or escape from nonsense-mediated decay (NMD-incompetent) based on the location of the conceptually translated premature termination codon (50 bp rule). Then for each gene, we counted the number of NMD-competent and NMD-incompetent variants and identified the genes that are enriched for NMD-incompetent variants compared to NMD-competent variants (unpublished results). REST represented one of the genes identified by this computational approach, having two distinct NMD-incompetent variants (the variants that were identified in both individuals with GF), but no NMD-competent variants in the CMG database. After we identified these extremely rare variants by two independent computational filtering analyses methods, we submitted REST to GeneMatcher, which is an online matching tool for connecting researchers with an interest in the same gene.13Sobreira N. Schiettecatte F. Valle D. Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene.Hum. Mutat. 2015; 36: 928-930Crossref PubMed Scopus (819) Google Scholar The GeneMatcher tool facilitated identification of family 3, which has an affected child (II-1 in Figure 1C) with GF. The female proband was initially evaluated at the Division of Medical Genetics Children’s Hospital of Orange County in California at 9 years of age due to gingival overgrowth. Other remarkable clinical findings of the affected individual were small hiatal hernia, pectus excavatum, short stature, and recurrent upper respiratory infections. Family 3 was sequenced by a trio approach and a de novo frameshift REST variant (GenBank: NM_005612.4; exon 4; c.2413delC [p.Leu805Phefs∗38]; chr4:57,797,436_CC>C; variant to total reads = 36/71) was identified (see Supplemental Note for detailed downstream WES). None of these three truncating alleles have been reported before in our CMG database or in other publicly available databases such as the Exome Aggregation Consortium (ExAC) database. To confirm and evaluate potential disease-associated variants for co-segregation with the phenotype in all family members, with available DNA, we performed conventional PCR. Exon four of REST was amplified from genomic DNA by using the primer sets provided in the Supplemental Note. The resulting PCR products were purified with ExoSAP-IT (Affymetrix) and sequenced using Sanger di-deoxy nucleotide sequencing. In family 1 both affected siblings (BAB4122, II-1 and BAB4125, II-2 in Figure 1A) were found to be heterozygous for the identified frameshift c.2865_2866delAA (p.Asn958Serfs∗9) variant allele and the mother was found to be wild-type (Figure 2A). The mildly affected father also appeared to contain two wild-type alleles by Sanger sequencing; however, the observed mild GF phenotype in the father suggested a possible tissue-specific mosaicism and transmission of the frameshift variant to the affected siblings from the father. To confirm the putative potential mosaicism, we collected a buccal smear sample from the father and subjected the isolated DNA to Sanger sequencing. The Sanger chromatogram result revealed evidence for subtle secondary peaks that begin at the position in the sequence of the frameshift mutation observed in the two affected children (Figure 2A). This observation in the buccal DNA sample from the father, in combination with the observation of both affected siblings sharing the same heterozygous rare variant allele, provides evidence suggesting mosaicism in the father. Additionally, we inspected all resultant variants in the BAM file of the exome-sequenced index case (BAB4122, II-1 in Figure 1A) with the Integrative Genomics Viewer14Thorvaldsdóttir H. Robinson J.T. Mesirov J.P. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration.Brief. Bioinform. 2013; 14: 178-192Crossref PubMed Scopus (4881) Google Scholar and we found a heterozygous SNP (rs3796529) nearby the frameshift variant; subsequent Sanger sequencing of blood DNA from all family members revealed that this SNP is informative as the father is homozygous, the affected brothers were heterozygous, and the mother was wild-type for the identified SNP (Figure S1). Moreover, we manually cloned the entire region encompassing the SNP and frameshift allele in the affected brothers; individual clonal colonies were sequenced by a standard Sanger capillary protocol. Using this method, we observed that the frameshift is in cis with the SNP in the affected brothers (Figure S1). This indicates that the father’s haplotype segregates with the mutant allele, providing further evidence that the mild GF present in the father is probably due to low-level mosaicism. In a further experiment to investigate mosaicism in the father, we performed restriction enzyme analysis on DNA from buccal and blood samples of the father and blood samples from the affected brothers and mother. This experimental approach yielded two bands in both affected brothers but not in the unaffected parents, including the father with suspected mosaicism (Figure S2). In family 2, Sanger sequencing revealed that all five available affected individuals, including the proband, two siblings, mother, and a maternal uncle (III-5, III-1, III-3, II-2, and II-6, respectively, in Figure 1B), were heterozygous carriers for the WES-identified stop-gain variant (c.1310T>A [p.Leu437∗]) and the unaffected maternal aunt (II-4 in Figure 1B) was wild-type at this locus (Figure 2A). In family 3 the de novo REST variant (c.2413delC [p.Leu805fsPhe∗38]) was identified in the proband (II-1 in Figure 1C) by a trio WES approach; it was also confirmed by Sanger sequencing (Figure 2A). From a clinical perspective, the proband in family 1 (BAB4122, II-1 in Figure 1A) had a more severe phenotype with the clinical findings of osteoporosis and osteomyelitis compared to his affected brother, and the proband (II-1 in Figure 1C) from family 3 had some additional clinical findings such as short stature first detected at age 12, hiatal hernia, and recurrent upper respiratory infections. Additionally, both brothers in family 1 (II-1 and II-2 in Figure 1A) as well as the proband in family 3 (II-1 in Figure 1C) had a pectus deformity. However, no other pathogenic variants that may potentially explain the additional findings observed in these individuals were identified during further examination of parsed and filtered WES data. REST is located on chromosome 4q12, consists of 4 exons, and encodes a 1,097-amino acid protein15Schoenherr C.J. Anderson D.J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.Science. 1995; 267: 1360-1363Crossref PubMed Scopus (925) Google Scholar, 16Chong J.A. Tapia-Ramírez J. Kim S. Toledo-Aral J.J. Zheng Y. Boutros M.C. Altshuller Y.M. Frohman M.A. Kraner S.D. Mandel G. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.Cell. 1995; 80: 949-957Abstract Full Text PDF PubMed Scopus (925) Google Scholar (Figures 2B and 2C). REST is a zinc finger protein that regulates gene expression throughout the body.16Chong J.A. Tapia-Ramírez J. Kim S. Toledo-Aral J.J. Zheng Y. Boutros M.C. Altshuller Y.M. Frohman M.A. Kraner S.D. Mandel G. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.Cell. 1995; 80: 949-957Abstract Full Text PDF PubMed Scopus (925) Google Scholar, 17Ooi L. Wood I.C. Chromatin crosstalk in development and disease: lessons from REST.Nat. Rev. Genet. 2007; 8: 544-554Crossref PubMed Scopus (312) Google Scholar It has a critical function as a transcriptional repressor during embryonic development and neurogenesis so it is also called neuron-restrictive silencer element.15Schoenherr C.J. Anderson D.J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.Science. 1995; 267: 1360-1363Crossref PubMed Scopus (925) Google Scholar Additionally, REST has different roles in several cellular mechanisms, such as oncogenic and tumor-suppressor functions, hematopoietic, cardiac and osteoblast differentiation, and effects on chromatin-modifying enzymes.17Ooi L. Wood I.C. Chromatin crosstalk in development and disease: lessons from REST.Nat. Rev. Genet. 2007; 8: 544-554Crossref PubMed Scopus (312) Google Scholar, 18Negrini S. Prada I. D’Alessandro R. Meldolesi J. REST: an oncogene or a tumor suppressor?.Trends Cell Biol. 2013; 23: 289-295Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 19Thakore-Shah K. Koleilat T. Jan M. John A. Pyle A.D. REST/NRSF knockdown alters survival, lineage differentiation and signaling in human embryonic stem cells.PLoS ONE. 2015; 10: e0145280Crossref PubMed Scopus (11) Google Scholar, 20Kuwahara K. Role of NRSF/REST in the regulation of cardiac gene expression and function.Circ. J. 2013; 77: 2682-2686Crossref PubMed Scopus (22) Google Scholar, 21Liu B. Cheng S. Xing W. Pourteymoor S. Mohan S. RE1-silencing transcription factor (Rest) is a novel regulator of osteoblast differentiation.J. Cell. Biochem. 2015; 116: 1932-1938Crossref PubMed Scopus (5) Google Scholar The pathophysiologic mechanisms underlying HGF remain enigmatic; however, excessive accumulation of extracellular matrix components, particularly collagen type I, seem to contribute to the clinical-pathologic manifestations.22Bonnaure-Mallet M. Tricot-Doleux S. Godeau G.J. Changes in extracellular matrix macromolecules in human gingiva after treatment with drugs inducing gingival overgrowth.Arch. Oral Biol. 1995; 40: 393-400Crossref PubMed Scopus (29) Google Scholar, 23Tipton D.A. Howell K.J. Dabbous M.K. Increased proliferation, collagen, and fibronectin production by hereditary gingival fibromatosis fibroblasts.J. Periodontol. 1997; 68: 524-530Crossref PubMed Scopus (61) Google Scholar, 24Martelli-Junior H. Cotrim P. Graner E. Sauk J.J. Coletta R.D. Effect of transforming growth factor-beta1, interleukin-6, and interferon-gamma on the expression of type I collagen, heat shock protein 47, matrix metalloproteinase (MMP)-1 and MMP-2 by fibroblasts from normal gingiva and hereditary gingival fibromatosis.J. Periodontol. 2003; 74: 296-306Crossref PubMed Scopus (76) Google Scholar In a comparative study performed on normal gingiva and HGF fibroblasts, Martelli-Junior et al. showed that the expression and production of type I collagen is significantly higher in fibroblasts from HGF than from normal gingiva.24Martelli-Junior H. Cotrim P. Graner E. Sauk J.J. Coletta R.D. Effect of transforming growth factor-beta1, interleukin-6, and interferon-gamma on the expression of type I collagen, heat shock protein 47, matrix metalloproteinase (MMP)-1 and MMP-2 by fibroblasts from normal gingiva and hereditary gingival fibromatosis.J. Periodontol. 2003; 74: 296-306Crossref PubMed Scopus (76) Google Scholar They also demonstrated that addition of TGF-β1 and IL-6, which are produced in greater amounts by HGF fibroblasts, promoted an increase in type 1 collagen. Type 1 collagen is the major component of the extracellular matrix which is produced in principal by fibroblasts and TGF-β and IL-6 have crucial roles in promoting the synthesis of the collagen together with other growth factors. Pathway analysis performed by Kong et al. showed that putative REST target genes were widely involved in TGF-β signaling and in the same study they showed that the inhibition of REST upregulates the TGF-β signaling pathway.25Kong Q.R. Xie B.T. Zhang H. Li J.Y. Huang T.Q. Wei R.Y. Liu Z.H. RE1-silencing transcription factor (REST) is required for nuclear reprogramming by inhibiting transforming growth factor β signaling pathway.J. Biol. Chem. 2016; 291: 27334-27342Crossref PubMed Scopus (6) Google Scholar Another study implemented on neurendocrine differentiation in prostate cancer cells revealed that knockdown of REST activates the IL-6-induced autopaghy pathway.26Chang P.C. Wang T.Y. Chang Y.T. Chu C.Y. Lee C.L. Hsu H.W. Zhou T.A. Wu Z. Kim R.H. Desai S.J. et al.Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells.PLoS ONE. 2014; 9: e88556Crossref PubMed Scopus (48) Google Scholar The authors also showed that IL-6-induced neuronal cell morphology changes in prostate cancer cells were significantly inhibited when there was REST overexpression. This finding was confirmed in a subsequent study by showing that the overexpression of exogenous REST abrogates IL-6-induced neuroendocrine differentiation in prostate cancer cells.27Zhu Y. Liu C. Cui Y. Nadiminty N. Lou W. Gao A.C. Interleukin-6 induces neuroendocrine differentiation (NED) through suppression of RE-1 silencing transcription factor (REST).Prostate. 2014; 74: 1086-1094Crossref PubMed Scopus (56) Google Scholar Taken together we can speculate that truncating mutations in REST may lead to overexpression of TGF-β and IL-6 that increase collagen type 1 synthesis in gingival tissue and results in GF. To show the profibrotic effects of TGFβ in gingival fibroblasts, Thompson et al. tested the effect of a specific pharmacological inhibitor of TGFβ type 1 receptor on the ability of TGFβ to induce connective tissue growth factor (which is a marker and mediator of fibrosis, not normally expressed in gingival fibroblasts, but is induced by the potent profibrotic cytokine TGFβ and is overexpressed in gingival fibrosis) in gingival fibroblasts.28Thompson K. Hamilton D.W. Leask A. ALK5 inhibition blocks TGFß-induced CCN2 expression in gingival fibroblasts.J. Dent. Res. 2010; 89: 1450-1454Crossref PubMed Scopus (26) Google Scholar Their results suggested that blocking TGFβ type 1 receptor may be useful in blocking the profibrotic effects of TGFβ in gingival fibroblasts. Dysregulation of REST has been implicated in diverse diseases such as Alzheimer disease (MIM: 104300), Huntington disease (MIM: 143100), and Down syndrome (MIM: 190685) and also in several malignancies.18Negrini S. Prada I. D’Alessandro R. Meldolesi J. REST: an oncogene or a tumor suppressor?.Trends Cell Biol. 2013; 23: 289-295Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 29Lu T. Aron L. Zullo J. Pan Y. Kim H. Chen Y. Yang T.H. Kim H.M. Drake D. Liu X.S. et al.REST and stress resistance in ageing and Alzheimer’s disease.Nature. 2014; 507: 448-454Crossref PubMed Scopus (479) Google Scholar, 30Zuccato C. Tartari M. Crotti A. Goffredo D. Valenza M. Conti L. Cataudella T. Leavitt B.R. Hayden M.R. Timmusk T. et al.Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.Nat. Genet. 2003; 35: 76-83Crossref PubMed Scopus (732) Google Scholar, 31Zhou Z. Yu L. Kleinerman E.S. EWS-FLI-1 regulates the neuronal repressor gene REST, which controls Ewing sarcoma growth and vascular morphology.Cancer. 2014; 120: 579-588Crossref PubMed Scopus (16) Google Scholar, 32Cho E. Moon S.M. Park B.R. Kim D.K. Lee B.K. Kim C.S. NRSF/REST regulates the mTOR signaling pathway in oral cancer cells.Oncol. Rep. 2015; 33: 1459-1464Crossref PubMed Scopus (16) Google Scholar, 33Taylor P. Fangusaro J. Rajaram V. Goldman S. Helenowski I.B. MacDonald T. Hasselblatt M. Riedemann L. Laureano A. Cooper L. Gopalakrishnan V. REST is a novel prognostic factor and therapeutic target for medulloblastoma.Mol. Cancer Ther. 2012; 11: 1713-1723Crossref PubMed Scopus (43) Google Scholar, 34Huang Z. Bao S. Ubiquitination and deubiquitination of REST and its roles in cancers.FEBS Lett. 2012; 586: 1602-1605Crossref PubMed Scopus (38) Google Scholar, 35Coulson J.M. Fiskerstrand C.E. Woll P.J. Quinn J.P. Arginine vasopressin promoter regulation is mediated by a neuron-restrictive silencer element in small cell lung cancer.Cancer Res. 1999; 59: 5123-5127PubMed Google Scholar, 36Lv H. Pan G. Zheng G. Wu X. Ren H. Liu Y. Wen J. Expression and functions of the repressor element 1 (RE-1)-silencing transcription factor (REST) in breast cancer.J. Cell. Biochem. 2010; 110: 968-974Crossref PubMed Scopus (30) Google Scholar, 37Westbrook T.F. Martin E.S. Schlabach M.R. Leng Y. Liang A.C. Feng B. Zhao J.J. Roberts T.M. Mandel G. Hannon G.J. et al.A genetic screen for candidate tumor suppressors identifies REST.Cell. 2005; 121: 837-848Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar, 38Coulson J.M. Transcriptional regulation: cancer, neurons and the REST.Curr. Biol. 2005; 15: R665-R668Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 39Bahn S. Mimmack M. Ryan M. Caldwell M.A. Jauniaux E. Starkey M. Svendsen C.N. Emson P. Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down’s syndrome: a gene expression study.Lancet. 2002; 359: 310-315Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 40Tawadros T. Martin D. Abderrahmani A. Leisinger H.J. Waeber G. Haefliger J.A. IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation.Cell. Signal. 2005; 17: 929-939Crossref PubMed Scopus (24) Google Scholar Recently, mutations in REST have been shown to predispose to Wilms tumor (MIM: 616806).41Mahamdallie S.S. Hanks S. Karlin K.L. Zachariou A. Perdeaux E.R. Ruark E. Shaw C.A. Renwick A. Ramsay E. Yost S. et al.Mutations in the transcriptional repressor REST predispose to Wilms tumor.Nat. Genet. 2015; 47: 1471-1474Crossref PubMed Scopus (44) Google Scholar The identified REST mutations in individuals with Wilms tumor were clustered within the zinc-finger DNA-binding domain of REST (Figure 2C). Interestingly, only one out of eleven variants mapped outside of the DNA-binding domain; a nonsense mutation (c.2770C>T [p.Gln924∗]) located in the final exon. The reported individual who carries this mutation is a girl who was diagnosed with Wilms tumor at 3.4 years of age and she has inherited the mutation from an unaffected parent. No other congenital abnormality has been reported for the affected child and no clinical data are available for the parent who transmitted the nonsense mutation. Lack of reported GF may be because the identified mutation in these individuals does not cause a gingival phenotype, or because the age of child is too early to observe GF and the parent was not examined for GF, or because the gingiva were not examined or noted on physical exam. Furthermore, Wilms tumor or any other malignancies were not detected to date in any of the individuals in our study. There are also some truncating variants reported in the last exon of REST in publicly available databases (i.e., ExAC). REST is predicted to be intolerant to loss-of-function alleles with a 0.97 pLI score42Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6551) Google Scholar in the ExAC database; however, since we do not have access to the samples from that database we cannot validate these putative truncating variants. The calling of indels in genome-wide sequencing remains a challenge because of poor mappability.43Wang Z. Liu X. Yang B.Z. Gelernter J. The role and challenges of exome sequencing in studies of human diseases.Front. Genet. 2013; 4: 160Crossref PubMed Scopus (70) Google Scholar Therefore, frameshift variants identified in exome/genome sequencing need to be confirmed with Sanger sequencing or allele-specific cloning. Additionally, and most importantly, we lack clinical information to check whether those individuals with truncating mutations have GF or not. The data from our computational algorithm that enabled an NMD prediction approach suggest that these truncating variants identified in BAB4122 (II-1 in Figure 1A) and BAB4235 (III-5 in Figure 1B) likely escape from NMD consistent with a hypothesis that such alleles may act through either a dominant-negative (antimorphic) or gain-of-function (neomorphic) effect, rather than by a haploinsufficiency mechanism. Thus, the mutant transcripts may reduce the repressor function of REST on the collagen synthesis pathway that results in the accumulation of collagen in gingiva. Nevertheless, without a biological experiment specifically designed for testing the effects of various truncating variants of REST, the mechanism of GF-causing mutations remains unclear. In this study, we describe three different heterozygous truncating variants, all of which are located in the final exon in REST, that cause autosomal-dominant HGF in three unrelated families. Interestingly, REST does not map to one of the four loci that have been previously associated with HGF. HGF is a rare disorder and sometimes, particularly the mild forms, can be overlooked during the physical examination and the affected individuals may not be referred to genetic clinics for diagnosis or further research studies. Therefore, we postulate that other genetic loci/genes remain to be identified. Further studies are needed to delineate the mutational spectrum and phenotype associations of both somatic and germline mutations in REST and to elucidate the role of REST in the molecular pathophysiology of HGF. We thank the families for participation in this study. This work was supported in part by funding from the National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHBLI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG, UM1 HG006542); NHGRI grant to Baylor College of Medicine Human Genome Sequencing Center (U54HG003273), National Institute of Neurological Disorders and Stroke (NINDS) (R01NS05829 to J.R.L.), and NHGRI, NHBLI, and NINDS, all Institutes of the United States NIH. J.R.L. has stock ownership in 23andMe and Lasergen, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered in the Baylor Genetics Laboratory. M.T.C. and A.B. are employees of GeneDx. The accession numbers for the variants (c.2865_2866delAA, c.1310T>A, and c.2413delC) reported in this paper are ClinVar: SCV000579327, SCV000579328, and SCV000579329. Download .pdf (.74 MB) Help with pdf files Document S1. Supplemental Note, Figures S1 and S2, and Table S1 1000 Genomes, http://www.internationalgenome.org/Atherosclerosis Risk in Communities Study (ARIC) Database, http://www2.cscc.unc.edu/aric/Baylor Genetics Laboratory, http://bmgl.com/cBioPortal for Cancer Genomics, http://www.cbioportal.org/ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/ExAC Browser, http://exac.broadinstitute.org/GenBank, http://www.ncbi.nlm.nih.gov/genbank/GeneMatcher, https://genematcher.org/IGV, http://www.broadinstitute.org/igv/Likelihood Ratio Test, http://www.genetics.wustl.edu/jflab/lrt_query.htmlMutationTaster, http://www.mutationtaster.org/NHLBI Exome Sequencing Project (ESP) Exome Variant Server, http://evs.gs.washington.edu/EVS/OMIM, http://www.omim.org/PolyPhen-2, http://genetics.bwh.harvard.edu/pph2/PROVEAN, http://provean.jcvi.orgUniProt, http://www.uniprot.org/" @default.
• W2731570147 created "2017-07-14" @default.
• W2731570147 creator A5000612576 @default.
• W2731570147 creator A5012914701 @default.
• W2731570147 creator A5023261072 @default.
• W2731570147 creator A5024872504 @default.
• W2731570147 creator A5029160247 @default.
• W2731570147 creator A5037749785 @default.
• W2731570147 creator A5042352338 @default.
• W2731570147 creator A5042504042 @default.
• W2731570147 creator A5042666128 @default.
• W2731570147 creator A5057929202 @default.
• W2731570147 creator A5058121685 @default.
• W2731570147 creator A5058160830 @default.
• W2731570147 creator A5059626751 @default.
• W2731570147 creator A5065420361 @default.
• W2731570147 creator A5066720834 @default.
• W2731570147 creator A5072413189 @default.
• W2731570147 creator A5073825641 @default.
• W2731570147 creator A5075068848 @default.
• W2731570147 creator A5079352402 @default.
• W2731570147 creator A5083240572 @default.
• W2731570147 creator A5085125040 @default.
• W2731570147 creator A5087129506 @default.
• W2731570147 date "2017-07-01" @default.
• W2731570147 modified "2023-10-14" @default.
• W2731570147 title "REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis" @default.
• W2731570147 cites W1536812836 @default.
• W2731570147 cites W1537922284 @default.
• W2731570147 cites W1808711893 @default.
• W2731570147 cites W1832759049 @default.
• W2731570147 cites W1971019770 @default.
• W2731570147 cites W1972937439 @default.
• W2731570147 cites W2001595883 @default.
• W2731570147 cites W2010541165 @default.
• W2731570147 cites W2012302769 @default.
• W2731570147 cites W2018647098 @default.
• W2731570147 cites W2028998065 @default.
• W2731570147 cites W2032023483 @default.
• W2731570147 cites W2036475318 @default.
• W2731570147 cites W2040184596 @default.
• W2731570147 cites W2040671431 @default.
• W2731570147 cites W2043913457 @default.
• W2731570147 cites W2047453840 @default.
• W2731570147 cites W2052620982 @default.
• W2731570147 cites W2060733408 @default.
• W2731570147 cites W2061000437 @default.
• W2731570147 cites W2061043894 @default.
• W2731570147 cites W2064050001 @default.
• W2731570147 cites W2074683462 @default.
• W2731570147 cites W2081077981 @default.
• W2731570147 cites W2085615042 @default.
• W2731570147 cites W2087099947 @default.
• W2731570147 cites W2091811407 @default.
• W2731570147 cites W2109159941 @default.
• W2731570147 cites W2117131162 @default.
• W2731570147 cites W2120580225 @default.
• W2731570147 cites W2127204575 @default.
• W2731570147 cites W2130122711 @default.
• W2731570147 cites W2132216401 @default.
• W2731570147 cites W2134482895 @default.
• W2731570147 cites W2134638008 @default.
• W2731570147 cites W2163127301 @default.
• W2731570147 cites W2165795426 @default.
• W2731570147 cites W2168918431 @default.
• W2731570147 cites W2183306400 @default.
• W2731570147 cites W2211303326 @default.
• W2731570147 cites W2253528038 @default.
• W2731570147 cites W2256016639 @default.
• W2731570147 cites W2554554198 @default.
• W2731570147 doi "https://doi.org/10.1016/j.ajhg.2017.06.006" @default.
• W2731570147 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5501868" @default.
• W2731570147 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28686854" @default.
• W2731570147 hasPublicationYear "2017" @default.
• W2731570147 type Work @default.
• W2731570147 sameAs 2731570147 @default.
• W2731570147 citedByCount "43" @default.
• W2731570147 countsByYear W27315701472018 @default.
• W2731570147 countsByYear W27315701472019 @default.
• W2731570147 countsByYear W27315701472020 @default.
• W2731570147 countsByYear W27315701472021 @default.
• W2731570147 countsByYear W27315701472022 @default.
• W2731570147 countsByYear W27315701472023 @default.
• W2731570147 crossrefType "journal-article" @default.
• W2731570147 hasAuthorship W2731570147A5000612576 @default.
• W2731570147 hasAuthorship W2731570147A5012914701 @default.
• W2731570147 hasAuthorship W2731570147A5023261072 @default.
• W2731570147 hasAuthorship W2731570147A5024872504 @default.
• W2731570147 hasAuthorship W2731570147A5029160247 @default.
• W2731570147 hasAuthorship W2731570147A5037749785 @default.
• W2731570147 hasAuthorship W2731570147A5042352338 @default.
• W2731570147 hasAuthorship W2731570147A5042504042 @default.
• W2731570147 hasAuthorship W2731570147A5042666128 @default.
• W2731570147 hasAuthorship W2731570147A5057929202 @default.
• W2731570147 hasAuthorship W2731570147A5058121685 @default.
• W2731570147 hasAuthorship W2731570147A5058160830 @default.
• W2731570147 hasAuthorship W2731570147A5059626751 @default.
• W2731570147 hasAuthorship W2731570147A5065420361 @default.

• next