Gene Summary

Gene:EXT1; exostosin glycosyltransferase 1
Summary:This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of multiple exostoses. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

EXT1 abnormalities are associated with hereditary multiple exostoses, an autosomal dominant bone disorder (also associated with EXT2 and EXT3 gene mutations). A small proportion of cases exhibit malignant transformation resulting in osteosarcoma or chondrosarcoma. Mutation of EXT1 has also been implicated in sporadic chondrosarcoma.

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA Primers
  • Gene Deletion
  • Cancer DNA
  • FISH
  • Mutation
  • Messenger RNA
  • Childhood Cancer
  • DNA Mutational Analysis
  • Chondrosarcoma
  • Syndecan-1
  • Asian Continental Ancestry Group
  • Bone Cancer
  • Chromosome 8
  • Wnt1 Protein
  • Cancer Gene Expression Regulation
  • Polymerase Chain Reaction
  • Adolescents
  • Single-Stranded Conformational Polymorphism
  • Chromosome Mapping
  • Osteosarcoma
  • China
  • Genotype
  • Restriction Mapping
  • N-Acetylglucosaminyltransferases
  • Heparitin Sulfate
  • Base Sequence
  • Gene Expression Profiling
  • Chromosome 11
  • Genetic Testing
  • Heterozygote
  • Exostoses, Multiple Hereditary
  • Genetic Linkage
  • exostosin-1
  • Loss of Heterozygosity
  • Exons
  • Osteochondroma
  • Amino Acid Sequence
  • Missense Mutation
  • Genetic Predisposition
  • Tumor Suppressor Gene
  • Frameshift Mutation
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Multiple Hereditary ExostosesEXT1 and Multiple Hereditary Exostoses View Publications162
ChondrosarcomaEXT1 mutations in Secondaty Chondrosarcoma
Osteochondroma (the most common type of benign bone tumor) is frequently characterised by mutations of EXT1 and EXT2 genes, often sporadic but sometimes germline, as seen in Multiple Hereditary Exostoses. Osteochondromas occasionally undergo neoplastic transformation resulting in secondary chondrosarcoma.
View Publications41
OsteosarcomaSecondary Osteosarcoma following Osteochondroma
In rare cases osteosarcoma has been reported following malignant transformation of osteochondroma / multiple hereditary exostoses.
View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: EXT1 (cancer-related)

Long X, Li Z, Huang Y, et al.
Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.
Medicine (Baltimore). 2019; 98(20):e15692 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder.
PATIENT CONCERNS: Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement.
DIAGNOSES: Hereditary multiple exostoses.
INTERVENTIONS: To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were used after genomic DNA was isolated from peripheral blood leucocytes. Point mutations identified by these methods were verified by Sanger sequencing after PCR amplification.
OUTCOMES: Six mutations in the EXT1 and EXT2 genes were identified, including a heterozygous deletion mutation from exon 2 to exon 8 (Family 1), a c.448C>T, p.(Gln150X) heterozygous nonsense mutation (Family 4), a c.1057-2A>T heterozygous splicing substitution (Family 5), and a c.1468dupC, p.(Leu490fs519X) (Family 6) heterozygous duplication mutation in the EXT1 gene in addition to a heterozygous deletion mutation from exon 2 to exon 3 (Family 2) and a c.1197C>G, p.(Tyr399X) heterozygous nonsense mutation (Family 3) in the EXT2 gene.
LESSONS: Overall, we identified 5 novel mutations and 1 recurrent mutation in the EXT1 and EXT2 genes in 6 Chinese families with HME. Our findings expand the mutational spectrum of the EXT1 and EXT2 genes and are useful for genetic counseling and prenatal diagnosis.

Bai Y, Liu N, Hu S, et al.
[Analysis of EXT1 and EXT2 gene mutations in two Chinese pedigrees affected with hereditary multiple exostosis].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019; 36(5):451-455 [PubMed] Related Publications
OBJECTIVE: To detect EXT1 and EXT2 gene mutations in two pedigrees affected with hereditary multiple exostosis (HME).
METHODS: The coding regions and exon/intron boundaries of the EXT1 and EXT2 genes were analyzed by targeted next-generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the probands, their family members and 200 unrelated healthy controls. Gross deletion was confirmed by quantitative PCR (qPCR) analysis and multiple ligation-dependent probe amplification (MLPA) analysis.
RESULTS: Two mutations were detected in the pedigrees, which included EXT2 gene c.337_338insG mutation in pedigree 1 and deletion of entire EXT1 in pedigree 2. Analysis of sequencing data revealed that a novel heterozygous mutation (c.337_338insG) in EXT2 gene in proband 1 and his father. The same mutation was not found among healthy family members and 200 unrelated healthy controls. As shown by NGS and MLPA analysis, proband 2 carried a heterozygous deletion of entire EXT1 gene. The same deletion was also found in her mother by qPCR.
CONCLUSION: Mutations of the EXT1 and EXT2 genes probably underlie the HME in both pedigrees. NGS combined with Sanger sequencing, qPCR and MLPA is effective for attaining the diagnosis.

Guo X, Lin M, Yan W, et al.
A novel splice mutation induces exon skipping of the EXT1 gene in patients with hereditary multiple exostoses.
Int J Oncol. 2019; 54(3):859-868 [PubMed] Free Access to Full Article Related Publications
The molecular mechanism of hereditary multiple exostoses (HME) remains ambiguous and a limited number of studies have investigated the pathogenic mechanism of mutations in patients with HME. In the present study, a novel heterozygous splice mutation (c.1284+2del) in exostosin glycosyltransferase 1 (EXT1) gene was identified in a three‑generation family with HME. Bioinformatics and TA clone‑sequencing indicated that the splice site mutation would result in exon 4 skipping. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) revealed that the expression levels of wild‑type EXT1/EXT2 mRNA in patients with HME were significantly decreased, compared with normal control participants (P<0.05). Abnormal EXT1 transcript lacking exon 4 (EXT1‑DEL) and full‑length EXT1 mRNA (EXT1‑FL) were overexpressed in 293‑T cells and Cos‑7 cells using lentivirus infection. RT‑qPCR demonstrated that the expression level of EXT1‑DEL was significantly increased, compared with EXT1‑FL (17.032 vs. 6.309, respectively; P<0.05). The protein encoded by EXT1‑DEL was detected by western blot analysis, and the level was increased, compared with EXT1‑FL protein expression. Immunofluorescence indicated that the protein encoded by EXT1‑DEL was located in the cytoplasm of Cos‑7 cells, which was consistent with the localization of the EXT1‑FL protein. In conclusion, the present study identified a novel splice mutation that causes exon 4 skipping during mRNA splicing and causes reduced expression of EXT1/EXT2. The mutation in EXT1‑DEL generated a unique peptide that is located in the cytoplasm in vitro, and it expands the mutation spectrum and provides molecular genetic evidence for a novel pathogenic mechanism of HME.

Oliver GR, Blackburn PR, Ellingson MS, et al.
RNA-Seq detects a SAMD12-EXT1 fusion transcript and leads to the discovery of an EXT1 deletion in a child with multiple osteochondromas.
Mol Genet Genomic Med. 2019; 7(3):e00560 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We describe a patient presenting with pachygyria, epilepsy, developmental delay, short stature, failure to thrive, facial dysmorphisms, and multiple osteochondromas.
METHODS: The patient underwent extensive genetic testing and analysis in an attempt to diagnose the cause of his condition. Clinical testing included metaphase karyotyping, array comparative genomic hybridization, direct sequencing and multiplex ligation-dependent probe amplification and trio-based exome sequencing. Subsequently, research-based whole transcriptome sequencing was conducted to determine whether it might shed light on the undiagnosed phenotype.
RESULTS: Clinical exome sequencing of patient and parent samples revealed a maternally inherited splice-site variant in the doublecortin (DCX) gene that was classified as likely pathogenic and diagnostic of the patient's neurological phenotype. Clinical array comparative genome hybridization analysis revealed a 16p13.3 deletion that could not be linked to the patient phenotype based on affected genes. Further clinical testing to determine the cause of the patient's multiple osteochondromas was unrevealing despite extensive profiling of the most likely causative genes, EXT1 and EXT2, including mutation screening by direct sequence analysis and multiplex ligation-dependent probe amplification. Whole transcriptome sequencing identified a SAMD12-EXT1 fusion transcript that could have resulted from a chromosomal deletion, leading to the loss of EXT1 function. Re-review of the clinical array comparative genomic hybridization results indicated a possible unreported mosaic deletion affecting the SAMD12 and EXT1 genes that corresponded precisely to the introns predicted to be affected by a fusion-causing deletion. The existence of the mosaic deletion was subsequently confirmed clinically by an increased density copy number array and orthogonal methodologies CONCLUSIONS: While mosaic mutations and deletions of EXT1 and EXT2 have been reported in the context of multiple osteochondromas, to our knowledge, this is the first time that transcriptomics technologies have been used to diagnose a patient via fusion transcript analysis in the congenital disease setting.

Li Y, Wang J, Tang J, et al.
Heterogeneous spectrum of EXT gene mutations in Chinese patients with hereditary multiple osteochondromas.
Medicine (Baltimore). 2018; 97(42):e12855 [PubMed] Free Access to Full Article Related Publications
Hereditary multiple osteochondroma (HMO) is one of the most common genetic skeletal disorders. It is caused by mutations in either EXT1 or EXT2 resulting in abnormal skeletal growth and morphogenesis. However, the spectrum and frequency of EXT1 and EXT2 mutations in Chinese patients with HMO was not previously investigated.Mutations were identified by performing Sanger sequencing analysis of the complete coding regions and flanking intronic sequences of EXT1 and EXT2, followed by multiplex ligation-dependent probe amplification (MLPA) analysis to detect gene deletions or duplications that could not be identified by the Sanger sequencing method.The present study identified pathogenic mutations in 93% (68/73) of unrelated HMO probands from 73 pedigrees. Mutations in EXT1 and EXT2 were identified in 53% (39/73) and 40% (29/73) of families. We identified 58 distinct mutations in EXT1 and EXT2, including 20 frameshift mutations, 16 nonsense mutations, 7 missense mutations, 9 splice site mutations, 5 large deletions, and 1 in-frame deletion mutation. Twenty-six of these mutations were novel and 32 were previously reported. Most of the mutations in EXT1 were base deletions or insertions (21/33), whereas the majority of those in EXT2 were single base substitution (18/25).Complete sequencing of both the EXT1 and EXT2 followed by MLPA analysis is recommended for genetic analysis of Chinese patients with HMO. This study provides a comprehensive characterization of the genetic aberrations found in Chinese patients with HMO and highlights the diagnostic value of molecular genetic analysis in this particular disease.

Dong S, Wu Y, Yu S, et al.
Increased EXT1 gene copy number correlates with increased mRNA level predicts short disease-free survival in hepatocellular carcinoma without vascular invasion.
Medicine (Baltimore). 2018; 97(39):e12625 [PubMed] Free Access to Full Article Related Publications
Exostosin-1 (EXT1) has been demonstrated to participate in the progression of many cancers. However, it has not been previously described in patients with hepatocellular carcinoma (HCC) without vascular invasion. In this study, we got the accurate data of EXT1 mRNA Z-score from the CBio data portal of The Cancer Genome Atlas (TCGA), which was used to express the level of EXT1 gene expression. We analyzed the EXT1 gene expression between HCC and normal liver tissue and compared the clinical significance of tumor tissue's EXT1 gene expression of HCC patients without vascular invasion based on data from TCGA database. The association between EXT1 gene expression and disease-free survival (DFS) was further analyzed. EXT1 gene copy number was also analyzed in this study. Univariate and multivariate analyses showed that high EXT1 gene expression group was significantly poorer than that of the low EXT1 gene expression group (P = .004). In addition, EXT1 gene expression was positively associated with α-fetoprotein (AFP), which is a well-known marker for HCC. There was a significant positive correlation between EXT1 copy number and upregulated EXT1 gene (P < .0001). In conclusion, upregulation of EXT1 could be an important indicator to the short DFS of HCC patients without vascular invasion. EXT1 gene copy number amplification is one of the mechanisms underlying the upregulation of EXT1.

Wu ZY, Wang Y, Wang JW, et al.
The role of EXT1 gene mutation and its high expression of calcitonin gene-related peptide in the development of multiple exostosis.
Biochem Biophys Res Commun. 2018; 505(4):959-965 [PubMed] Related Publications
OBJECTIVE: Screening and identifying the gene mutation of EXT1, EXT2 and EXT3 associated with multiple exostosis (ME) and the expression in tumor tissues.
METHODS: Nine patients with multiple exostosis were collected and genomic DNA was extracted. Polymerase chain reaction (PCR) amplification and direct sequencing techniques were used to screen all exons, 5' and 3' ends of the EXT1, EXT2 and EXT3 related causative genes. EXT1, EXT2 and EXT3 gene were screened and quantified by RNA-SEQ and RT-qPCR. The concentration of calcitonin gene-related peptide (CGRP) in peripheral blood of tumor patients and normal controls was detected by ELISA.
RESULTS: Between the two patients with ME, the EXT1 gene was found in one patient to have c.79 T>A mutation, which caused the change of p.M27T, the non polar methionine was replaced by the high frequency mutation of polar threonine, and the rest of patients was found the splicing mutation c.1284 + 8 delAT of the heterozygosity of the EXT1 gene. The serum CGRP concentration of ME patients (623 + 49 pg/ml) was significantly higher than that of normal controls (196 + 68 pg/ml), and EXT1 mutation patients were also higher than non mutation patients.

Cammarata-Scalisi F, Stock F, Avendaño A, et al.
[Clinical and molecular study in a family with multiple osteochondromatosis].
Acta Ortop Mex. 2018 Mar-Apr; 32(2):108-111 [PubMed] Related Publications
We present two cases of a family with the diagnosis of multiple osteochondromatosis, which was confirmed by molecular study with nonsense in heterozygosis mutation c.1219CT, (p.Gln407Stop) in the EXT1 gene. In these cases, the Madelung deformity was presented in one patient as an uncommon finding and chondrosarcoma as a feared complication in the other case, highlighting intrafamilial variation, which is why individual and interdisciplinary evaluation is recommended. In addition, before a genetic entity should provide adequate and timely family genetic counseling to all its members.

Chen Z, Bi Q, Kong M, Chen Y
A Novel EXT1 Mutation Identified in a Family with Multiple Osteochondromas.
Genet Test Mol Biomarkers. 2019; 23(4):251-254 [PubMed] Related Publications
AIMS: Multiple exostoses (MO), also referred to as hereditary multiple exostoses (HME), is an autosomal dominant inherited skeletal disorder that has been found to be associated with mutations in the EXT1 and EXT2 genes. In the present study, we report a Chinese family with HME and our mutational analyses of the EXT1 and EXT2 genes in affected and unaffected individuals.
METHODS: All exons of the EXT1 and EXT2 genes in seven family members were polymerase chain reaction amplified from blood and sequenced.
RESULTS: A heterozygous mutation (c.1056G>T) was identified in exon 2 of the EXT1 gene in the proband and other affected family members; this mutation was not found in the unaffected family members.
DISCUSSION: This c.1056G>T mutation is located in the exostosin domain of the EXT1 protein and leads to an amino acid change of Glutamine (Gln) to Histidine (His) at position 352. Homology searches reveal that Gln352 is highly conserved in many species and may play an essential role in the normal function of the EXT1 protein.
CONCLUSIONS: This study contributes to a better understanding of the genetic basis of HME, expands the known mutational spectrum of EXT1, and provides a reference for genetic counseling and prenatal diagnosis of this family.

Piombo V, Jochmann K, Hoffmann D, et al.
Signaling systems affecting the severity of multiple osteochondromas.
Bone. 2018; 111:71-81 [PubMed] Related Publications
Multiple osteochondromas (MO) syndrome is a dominant autosomal bone disorder characterized by the formation of cartilage-capped bony outgrowths that develop at the juxtaposition of the growth plate of endochondral bones. MO has been linked to mutations in either EXT1 or EXT2, two glycosyltransferases required for the synthesis of heparan sulfate (HS). The establishment of mouse mutants demonstrated that a clonal, homozygous loss of Ext1 in a wild type background leads to the development of osteochondromas. Here we investigate mechanisms that might contribute to the variation in the severity of the disease observed in human patients. Our results show that residual amounts of HS are sufficient to prevent the development of osteochondromas strongly supporting that loss of heterozygosity is required for osteochondroma formation. Furthermore, we demonstrate that different signaling pathways affect size and frequency of the osteochondromas thereby modulating the severity of the disease. Reduced Fgfr3 signaling, which regulates proliferation and differentiation of chondrocytes, increases osteochondroma number, while activated Fgfr3 signaling reduces osteochondroma size. Both, activation and reduction of Wnt/β-catenin signaling decrease osteochondroma size and frequency by interfering with the chondrogenic fate of the mutant cells. Reduced Ihh signaling does not change the development of the osteochondromas, while elevated Ihh signaling increases the cellularity and inhibits chondrocyte differentiation in a subset of osteochondromas and might thus predispose osteochondromas to the transformation into chondrosarcomas.

Santos SCL, Rizzo IMPO, Takata RI, et al.
Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas.
Mol Genet Genomic Med. 2018; 6(3):382-392 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%-90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population.
METHODS: DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families.
RESULTS: Germline variants were identified in 83% of families in which EXT2 variants were detected in 46% and EXT1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT2. Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT1 and 11 out of 17 (64.7%) EXT2 alleles. The vast majority of variants (88%) were "loss-of-function" and two novel hotspots in EXT2 gene were observed in our study.
CONCLUSION: The prevalence of variants detected in the EXT2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil.

Lou G, Yang K, Qin L, et al.
[Identification of a novel EXT1 mutation in a pedigree affected with hereditary multiple exostosis].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2018; 35(1):91-95 [PubMed] Related Publications
OBJECTIVE To detect potential mutations of the EXT1 and EXT2 genes in a pedigree affected with hereditary multiple exostosis (HME). METHODS For a four-generation family with 7 affected individuals from 17 family members,genomic DNA was extracted from peripheral venous blood samples. All exons of the EXT1 and EXT2 genes were screened for potential mutation by PCR and Sanger sequencing. RESULTS A novel heterozygous frameshift mutation c.1202delT (p.I401Tfs*2)was found in exon 4 of the EXT1 gene in the proband and the other 6 affected individuals. The same mutation was not detected among the healthy members from the family. The mutation has given rise a truncated EXT1 protein with loss of 345 amino acids. CONCLUSION A novel frameshift mutation of the EXT1 gene has been identified in a pedigree affected with HME, which has enriched the mutational spectrum of the EXT1 gene and may facilitate genetic counseling and prenatal diagnosis for the family.

Pacifici M
The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses.
Matrix Biol. 2018; 71-72:28-39 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Heparan sulfate (HS) is an essential component of cell surface and matrix proteoglycans (HS-PGs) that include syndecans and perlecan. Because of their unique structural features, the HS chains are able to specifically interact with signaling proteins -including bone morphogenetic proteins (BMPs)- via their HS-binding domain, regulating protein availability, distribution and action on target cells. Hereditary Multiple Exostoses (HME) is a rare pediatric disorder linked to germline heterozygous loss-of-function mutations in EXT1 or EXT2 that encode Golgi-resident glycosyltransferases responsible for HS synthesis, resulting in a systemic HS deficiency. HME is characterized by cartilaginous/bony tumors -called osteochondromas or exostoses- that form within perichondrium in long bones, ribs and other elements. This review examines most recent studies in HME, framing them in the context of classic studies. New findings show that the spectrum of EXT mutations is larger than previously realized and the clinical complications of HME extend beyond the skeleton. Osteochondroma development requires a somatic "second hit" that would complement the germline EXT mutation to further decrease HS production and/levels at perichondrial sites of osteochondroma induction. Cellular studies have shown that the steep decreases in local HS levels: derange the normal homeostatic signaling pathways keeping perichondrium mesenchymal; cause excessive BMP signaling; and provoke ectopic chondrogenesis and osteochondroma formation. Data from HME mouse models have revealed that systemic treatment with a BMP signaling antagonist markedly reduces osteochondroma formation. In sum, recent studies have provided major new insights into the molecular and cellular pathogenesis of HME and the roles played by HS deficiency. These new insights have led to the first ever proof-of-principle demonstration that osteochondroma formation is a druggable process, paving the way toward the creation of a clinically-relevant treatment.

Li Y, Wang J, Wang Z, et al.
A genotype-phenotype study of hereditary multiple exostoses in forty-six Chinese patients.
BMC Med Genet. 2017; 18(1):126 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Hereditary multiple exostoses (HME) is a rare autosomal dominant skeletal disorder that can cause a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of HME by using a scoring system and correlate the genotypes with different clinical phenotypes in Chinese patients.
METHODS: Forty-six patients from different families were prospectively enrolled. The mutations were identified by direct sequencing of PCR-amplified genomic DNA or by multiplex ligation-dependent probe amplification (MLPA). Patients' demographic data, height, age of onset, number of anatomical sites, forearm deformity, and lower extremity alignment were analysed according to genotype and gender. A scoring system was used to assess the severity of the clinical phenotype.
RESULTS: Thirty (60%) patients presented mutations in the EXT1 gene, and 16 (32%) presented mutations in the EXT2 gene. The mean age of onset was 2.96 years. The mean number of involved anatomic sites was 15.35. Male patients had more lesion sites than female patients (15.97 vs. 13.77, p = 0.046). The height evaluation illustrated that 67% of the patients (31 of 46) were below the 50th percentile, and the patients with EXT1 mutations were shorter than those with EXT2 mutations (p = 0.005). Forearm deformity showed a significant correlation with the number of involved anatomical sites (r = 0.382, p = 0.009). Moreover, a higher total score was found in patients with EXT1 mutations (p = 0.001).
CONCLUSIONS: The clinical manifestations of 46 Chinese HME patients were similar to those in previous reports of Western populations. Patients with EXT1 mutations have a more severe clinical phenotype than patients with EXT2 mutations.

Ushakov VS, Tsidulko AY, de La Bourdonnaye G, et al.
Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation.
Int J Mol Sci. 2017; 18(11) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Heparan sulfate (HS) is an important component of the extracellular matrix and cell surface, which plays a key role in cell-cell and cell-matrix interactions. Functional activity of HS directly depends on its structure, which determined by a complex system of HS biosynthetic enzymes. During malignant transformation, the system can undergo significant changes, but for glioma, HS biosynthesis has not been studied in detail. In this study, we performed a comparative analysis of the HS biosynthetic system in human gliomas of different grades. RT-PCR analysis showed that the overall transcriptional activity of the main HS biosynthesis-involved genes (

Medek K, Zeman J, Honzík T, et al.
Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families.
Prague Med Rep. 2017; 118(2-3):87-94 [PubMed] Related Publications
Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations in EXT1 and EXT2 genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA in EXT1 and EXT2 genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2-10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient developed malignant transformation. In half of the patients, the disease resulted in short stature. DNA analyses were positive in 7 families. In five probands, different EXT1 gene mutations resulting in premature stop-codon (p.Gly124Argfs*65, p.Leu191*, p.Trp364Lysfs*11, p.Val371Glyfs*10, p.Leu490Profs*31) were found. In two probands, nonsense mutations were found in EXT2 gene (p.Val187Profs*115, p.Cys319fs*46). Five mutations have been novel and two mutations have occurred de novo in probands. Although the risk for malignant transformation is usually low, especially in patients with low number of exostoses, early diagnostics and longitudinal follow up of patients is of a big importance, because early surgery can prevent progression of secondary bone deformities.

Xu Y, Kang Q, Zhang Z
Identification of mutations in EXT1 and EXT2 genes in six Chinese families with multiple osteochondromas.
Mol Med Rep. 2017; 16(4):5599-5605 [PubMed] Related Publications
The aim of the present study was to identify mutations of major causative genes in six unrelated Chinese families with multiple osteochondromas (MO). Radiographic examinations and genetic analyses were performed in 8 patients exhibiting typical features of MO. Analysis was also performed on unaffected members of the six families and 250 healthy volunteers. Radiographies of the patients revealed multiple exostoses in the cartilage of long bones. A total of five different mutations were identified, one in exostosin‑1 (EXT1) and four in exostosin‑2 (EXT2). Two novel mutations were detected in EXT2: A missense mutation, c.1385G>A, in exon 8, resulting in p.Trp462X; and a splice site mutation, c.725+1G>C, which consisted of a heterozygous guanine‑to‑cytosine transition at nucleotide 725+1 in intron 3. Three common EXT mutations were also detected: c.1036C>T in exon 5 of EXT2 resulting in p.Gln346X; c.1299C>A in exon 8 of EXT2 resulting in p.Phe433Leu; and c.1038A>T in exon 2 of EXT1 resulting in p.Arg346Ser. In conclusion, the present study identified a novel missense mutation (c.1385G>A) in exon 8 and a splicing mutation (c.725+1G>C) in intron 3 of the EXT2 gene, which are responsible for MO in certain Chinese patients. The findings are useful for expanding the database of known EXT2 mutations and understanding the genetic basis of MO in Chinese patients, which may improve genetic counseling and the prenatal diagnosis of MO.

Guo X, Chen W, Lin M, et al.
[Analysis of a multiple osteochondroma case caused by novel splice mutation (c.1164+1G to A) of EXT1 gene].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2017; 34(3):411-415 [PubMed] Related Publications
OBJECTIVE: To detect potential mutation of EXT1 gene in a pedigree affected with multiple osteochondroma and explore its pathogenic mechanism.
METHODS: The coding regions and their flanking sequences of the EXT1/EXT2 genes were subjected to PCR amplification and Sanger sequencing. Suspected mutations were verified by excluding possible single nucleotide polymorphisms and bioinformatics analysis. Transcripts of the EXT1 gene in the proband were analyzed by TA clone-sequencing, with its abundance compared with that of healthy controls.
RESULTS: DNA sequencing has identified in the proband a novel heterozygous point mutation (c.1164+1G to A) at the 5'splice sites of intron 3 of the EXT1 gene. The same mutation was not found in the healthy controls. Bioinformatics analysis indicated that the mutation is highly conserved and can lead to skipping of exon 3 or aberrant splicing. TA clone-sequencing indicated that the numbers of transcripts with skipping of exon 3 has significantly increased in the proband (< 0.05) compared with the controls.
CONCLUSION: The c.1164+1G to A mutation has resulted in skipping of exon 3 in a proportion of EXT1 gene transcripts. As the result, the number of transcripts with tumor suppressing function is relatively reduced and has ultimately led to the tumors.

Pacifici M
Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments.
Curr Osteoporos Rep. 2017; 15(3):142-152 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE OF REVIEW: Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention.
RECENT FINDINGS: Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.

Sinha S, Mundy C, Bechtold T, et al.
Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice.
PLoS Genet. 2017; 13(4):e1006742 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Hereditary Multiple Exostoses (HME) is a rare pediatric disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME is characterized by formation of cartilaginous outgrowths-called osteochondromas- next to the growth plates of many axial and appendicular skeletal elements. Surprisingly, it is not known whether such tumors also form in endochondral elements of the craniofacial skeleton. Here, we carried out a retrospective analysis of cervical spine MRI and CT scans from 50 consecutive HME patients that included cranial skeletal images. Interestingly, nearly half of the patients displayed moderate defects or osteochondroma-like outgrowths in the cranial base and specifically in the clivus. In good correlation, osteochondromas developed in the cranial base of mutant Ext1f/f;Col2-CreER or Ext1f/f;Aggrecan-CreER mouse models of HME along the synchondrosis growth plates. Osteochondroma formation was preceded by phenotypic alteration of cells at the chondro-perichondrial boundary and was accompanied by ectopic expression of major cartilage matrix genes -collagen 2 and collagen X- within the growing ectopic masses. Because chondrogenesis requires bone morphogenetic protein (BMP) signaling, we asked whether osteochondroma formation could be blocked by a BMP signaling antagonist. Systemic administration with LDN-193189 effectively inhibited osteochondroma growth in conditional Ext1-mutant mice. In vitro studies with mouse embryo chondrogenic cells clarified the mechanisms of LDN-193189 action that turned out to include decreases in canonical BMP signaling pSMAD1/5/8 effectors but interestingly, concurrent increases in such anti-chondrogenic mechanisms as pERK1/2 and Chordin, Fgf9 and Fgf18 expression. Our study is the first to reveal that the cranial base can be affected in patients with HME and that osteochondroma formation is amenable to therapeutic drug intervention.

Hong G, Guo X, Yan W, et al.
Identification of a novel mutation in the EXT1 gene from a patient with multiple osteochondromas by exome sequencing.
Mol Med Rep. 2017; 15(2):657-664 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Multiple osteochondromas (MO) is an autosomal skeletal disease with an elusive molecular mechanism. To further elucidate the genetic mechanism of the disease a three‑generation Chinese family with MO was observed and researched, and a novel frameshift mutation (c.335_336insA) in the exotosin 1 (EXT1) gene of one patient with MO was observed through exome sequencing. This was further validated by Sanger sequencing and comparison with 200 unrelated healthy controls. Immunohistochemistry and multiple sequence alignment were performed to determine the pathogenicity of the candidate mutation. Multiple sequence alignment suggested that codon 335 and 336 in the EXT1 gene were highly conserved regions in vertebrates. Immunohistochemistry revealed that EXT1 protein expression levels were decreased in a patient with MO and this mutation compared with a patient with MO who had no EXT1 mutation. Owing to the appearance of c.335_336insA in exon 1 of EXT1, a premature stop codon was introduced, resulting in truncated EXT1. As a result integrated and functional EXT1 was reduced. EXT1 is involved in the biosynthesis of heparan sulfate (HS), an essential molecule, and its dysfunction may lead to MO. The novel mutation of c.335_336insA in the EXT1 gene reported in the present study has enlarged the causal mutation spectrum of MO, and may assist genetic counseling and prenatal diagnosis of MO.

Cousminer DL, Arkader A, Voight BF, et al.
Assessing the general population frequency of rare coding variants in the EXT1 and EXT2 genes previously implicated in hereditary multiple exostoses.
Bone. 2016; 92:196-200 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Hereditary multiple exostoses (HME) is a rare childhood-onset skeletal disease linked to mutations in exostosin glycosyltransferase 1 (EXT1) or 2 (EXT2). Patients are heterozygous for either an EXT1 or EXT2 mutation, and it is widely assumed that exostosis formation and associated defects, such as growth retardation and skeletal deformities, require loss-of-heterozygosity or a second hit in affected cells. However, the relevance and phenotypic impact of many presumed pathogenic EXT variants remain uncertain. We extracted all amino acid-altering (missense) and loss of function (LoF; nonsense, frameshift, or splice-site) variants from the Exome Aggregation Consortium (ExAC), a large population-based repository of exome sequence data from diverse ancestries that has screened out severe pediatric disease, to assess the overall mutation spectrum of predicted protein-damaging variants across these two genes in the general population. We then determined whether clinically-identified, presumably pathogenic variants implicated in HME exist among healthy individuals. We found six EXT1 and four EXT2 missense mutations in ExAC, suggesting that these mutations have either been misclassified as pathogenic or are not fully penetrant. Furthermore, EXT1 is heavily selectively constrained, while EXT2 is more tolerant to protein-damaging variants, especially at its C-terminus, possibly explaining the genotype-phenotype correlation that EXT1 variants usually result in more severe disease. In conclusion, population-based exome data is a useful filter for determining whether clinically detected variants are likely pathogenic, as well as revealing biological insight into rare disease genes such as EXT1 and EXT2.

Legare JM, Modaff P, Iskandar BJ, Pauli RM
Syringomyelia in hereditary multiple exostosis.
Am J Med Genet A. 2016; 170(11):2956-2959 [PubMed] Related Publications
We describe five children with Hereditary Multiple Exostosis (HME) who also had syringomyelia. Of these, four had a tethered cord/fibrolipoma. No spinal osteochondromas were found in these patients. All had antecedent neurological signs or symptoms that prompted spinal imaging with MRI. Of all patients with HME seen in the Midwest Regional Bone Dysplasia Clinic from 1982 to present, 44% (17/39) of patients had signs or symptoms concerning for possible cord-related neurological findings. However, only 10 of 39 had spinal imaging. Assuming that all individuals with syringomyelia were identified, then 5/39 (13%) were in that way affected. This, of course, is a minimal estimate given that many were not imaged. The incidence of syringomyelia appears to be increased in this population, and seems to be unrelated to spinal osteochondromas. A low threshold for obtaining spinal MRI in patients with Hereditary Multiple Exostosis seems rational. © 2016 Wiley Periodicals, Inc.

Daakour S, Hajingabo LJ, Kerselidou D, et al.
Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
BMC Cancer. 2016; 16:335 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Perturbed genotypes in cancer can now be identified by whole genome sequencing of large number of diverse tumor samples, and observed gene mutations can be used for prognosis and classification of cancer subtypes. Although mutations in a few causative genes are directly linked to key signaling pathways perturbation, a global understanding of how known cancer genes drive oncogenesis in human is difficult to assess.
METHODS: We collected available information about mutated genes in Acute Lymphoblastic Leukemia (ALL). Validated human protein interactions (PPI) were collected from IntAct, HPRD and BioGRID interactomics databases, or obtained using yeast two-hybrid screening assay.
RESULTS: We have mapped interconnections between 116 cancer census gene products associated with ALL. Combining protein-protein interactions data and cancer-specific gene mutations information, we observed that 63 ALL-gene products are interconnected and identified 37 human proteins interacting with at least 2 ALL-gene products. We highlighted exclusive and coexistence genetic alterations in key signaling pathways including the PI3K/AKT and the NOTCH pathways. We then used different cell lines and reporter assay systems to validate the involvement of EXT1 in the Notch pathway.
CONCLUSION: We propose that novel ALL-gene candidates can be identified based on their functional association with well-known cancer genes. We identified EXT1, a gene not previously linked to ALL via mutations, as a common interactor of NOTCH1 and FBXW7 regulating the NOTCH pathway in an FBXW7-dependend manner.

Ishimaru D, Gotoh M, Takayama S, et al.
Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas.
BMC Genet. 2016; 17:52 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Multiple osteochondroma (MO) is an autosomal dominant skeletal disorder characterized by the formation of multiple osteochondromas, and exostosin-1 (EXT1) and exostosin-2 (EXT2) are major causative genes in MO. In this study, we evaluated the genetic backgrounds and mutational patterns in Japanese families with MO.
RESULTS: We evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. The exons and exon/intron junctions of EXT1 and EXT2 were directly sequenced after PCR amplification. Fifty-two mutations in 47 families with MO in either EXT1 or EXT2, and 42.3% (22/52) of mutations were novel mutations. Twenty-nine families (40.8%) had mutations in EXT1, and 15 families (21.1%) had mutations in EXT2. Interestingly, three families (4.2%) had mutations in both EXT1 and EXT2. Twenty-four families (33.8%) did not exhibit mutations in either EXT1 or EXT2. With regard to the types of mutations identified, 59.6% of mutations were inactivating mutations, and 38.5% of mutations were missense mutations.
CONCLUSIONS: We found that the prevalence of EXT1 mutations was greater than that of EXT2 mutations in Japanese MO families. Additionally, we identified 22 novel EXT1 and EXT2 mutations in this Japanese MO cohort. This study represents the variety of genotype in MO.

Tanteles GA, Nicolaou M, Neocleous V, et al.
Genetic screening of EXT1 and EXT2 in Cypriot families with hereditary multiple osteochondromas.
J Genet. 2015; 94(4):749-54 [PubMed] Related Publications

Musso N, Caronia FP, Castorina S, et al.
Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas.
Cancer Genet. 2015; 208(3):62-7 [PubMed] Related Publications
Multiple osteochondromas (MO) is an autosomal-dominant skeletal disorder caused by mutations in the exostosin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we report the analysis of the mutational status of the EXT2 gene in tumor samples derived from a patient affected by hereditary MO, documenting the somatic loss of the germline mutation in a giant chondrosarcoma and in a rapidly growing osteochondroma. The sequencing of all exons and exon-intron junctions of the EXT1 and EXT2 genes from blood DNA of the proband did not reveal any mutation in the EXT1 gene but did demonstrate the presence of the transition point mutation c.67C > T in the EXT2 gene, determining the introduction of a stop codon in the coding sequence (p.Arg23*). A mutational analysis of other members of the family and the presence of osteochondromas in the metaphysis of long bones confirmed the diagnosis of hereditary multiple osteochondromas. Direct sequencing from DNA extracted from different sites of two tumor samples (a small rapidly growing osteochondroma and a giant peripheral secondary chondrosarcoma, each located at different chondrocostal junctions) revealed the loss of the germline EXT2 mutation. Analysis of microsatellite polymorphic markers in the 11p region harboring the EXT2 gene did not reveal any loss of heterozygosity. This observation supports a recent model of sarcomagenesis in which osteochondroma cells bear EXT homozygous inactivation, whereas chondrosarcoma-initiating cells are EXT-expressing cells.

Cammarata-Scalisi F, Cozar M, Grinberg D, et al.
[Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses].
Arch Argent Pediatr. 2015; 113(2):e109-12 [PubMed] Related Publications
Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

de Andrea CE, Zhu JF, Jin H, et al.
Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency.
J Pathol. 2015; 236(2):210-8 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Peripheral chondrosarcoma (PCS) develops as malignant transformation of an osteochondroma, a benign cartilaginous outgrowth at the bone surface. Its invasive, lobular growth despite low-grade histology suggests a loss of chondrocyte polarity. The known genetics of osteochondromagenesis include mosaic loss of EXT1 or EXT2 in both hereditary and non-hereditary cases. The most frequent genetic aberrations in human PCS also include disruptions of CDKN2A or TP53. In order to test the sufficiency of either of these to drive progression of an osteochondroma to PCS, we added conditional loss of Trp53 or Ink4a/Arf in an Ext1-driven mouse model of osteochondromagenesis. Each additional tumour suppressor silencing efficiently drove the development of growths that mimic human PCS. As in humans, lobules developed from both Ext1-null and Ext1-functional clones within osteochondromas. Assessment of their orientation revealed an absence of primary cilia in the majority of mouse PCS chondrocytes, which was corroborated in human PCSs. Loss of primary cilia may be responsible for the lost polarity phenotype ascribed to PCS. Cilia deficiency blocks proliferation in physeal chondrocytes, but cell cycle deregulation is sufficient to rescue chondrocyte proliferation following deciliation. This provides a basis of selective pressure for the frequent cell-cycle regulator silencing observed in peripheral chondrosarcomagenesis. Mosaic loss of Ext1 combined with loss of cell cycle regulators promotes peripheral chondrosarcomagenesis in the mouse and reveals deficient ciliogenesis in both the model and the human disease, explaining biological behaviour including lobular and invasive growth.

Malini K, Gudi NS, Kutty AV, Balakrishna S
Mutational Analysis of Exostosin 1 and 2 Genes in Multiple Osteochondroma.
Indian J Pediatr. 2015; 82(7):649-50 [PubMed] Related Publications

Bovée JV, Sakkers RJ, Geirnaerdt MJ, et al.
Intermediate grade osteosarcoma and chondrosarcoma arising in an osteochondroma. A case report of a patient with hereditary multiple exostoses.
J Clin Pathol. 2002; 55(3):226-9 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
A 40 year old man with hereditary multiple exostoses (HME), affecting predominantly his left proximal tibia, distal femur, and proximal femur, underwent resection of an osteochondroma near the trochanter major of his left proximal femur because of malignant transformation of the cartilaginous cap towards secondary peripheral chondrosarcoma. The patient had a history of a papillary thyroid carcinoma four years previously. At examination of the resected specimen, a third malignant tumour, an intermediate grade osteosarcoma (grade II/IV), was found in the osseous stalk of the osteochondroma. Although no mutations were found in the EXT1 and EXT2 genes, the genes involved in HME, or in exons 5-8 of the p53 gene, the development of three malignancies before the age of 40 suggests that this patient is genetically prone to malignant transformation.

Engel EE, Nogueira-Barbosa MH, Brassesco MS, et al.
Osteosarcoma arising from osteochondroma of the tibia: case report and cytogenetic findings.
Genet Mol Res. 2012; 11(1):448-54 [PubMed] Related Publications
Osteochondroma is a cartilage capped benign tumor developing mainly at the juxta-epiphyseal region of long bones. The rate of malignant transformation, mainly into chondrosarcoma, is estimated to be less than 1-3%. Transformation into osteosarcoma is very rare and has been reported only thirteen times. There is little information on treatment and outcome. We report the case of a secondary osteosarcoma arising in the left tibia of a 23-year-old male, 10 years after the initial diagnosis of osteochondroma and after two partial resections. Malignant transformation occurred at the stalk and not at the cartilage cap, as would normally be expected. Chromosome banding analysis revealed the karyotype: 46,XY, t(3;13)(q21;q34) [2]/46,XY [18]. Records from additional cases will help determine the parameters that define these rare secondary bone lesions.

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