Alternative titles; symbols
HGNC Approved Gene Symbol: EXT1
SNOMEDCT: 1163016002, 254044004, 443520009; ICD10CM: Q78.6;
Cytogenetic location: 8q24.11 Genomic coordinates (GRCh38) : 8:117,794,490-118,111,826 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.11 | Chondrosarcoma | 215300 | Somatic mutation | 3 |
| Exostoses, multiple, type 1 | 133700 | Autosomal dominant | 3 |
EXT1 and EXT2 (608210) form a heterooligomeric complex that catalyzes the polymerization of heparan sulfate. This complex is an essential factor in a signal transduction cascade for regulation of chondrocyte differentiation, ossification, and apoptosis (summary by Heinritz et al., 2009).
By screening a human chondrocyte cDNA library with cosmids that spanned breakpoints on chromosome 8q identified in patients with multiple exostoses type I (EXT1; 133700) (see Ludecke et al., 1995), Ahn et al. (1995) identified a cDNA encoding a putative 746-amino acid protein with a molecular mass of 86.3 kD. Northern blot analysis detected expression of a 3.4-kb transcript in all tissues tested, with highest levels in liver. The authors noted that the breakpoint region in the EXT1 gene contains 2 identical polypyrimidine tracts (CCCCCCT) that are known to be deletion hotspots, similar to the retinoblastoma gene (RB1; 614041) (Lohmann et al., 1994).
Lin and Wells (1997) cloned and sequenced a mouse cDNA that is homologous to the human EXT1 gene. Lohmann et al. (1997) showed that the murine Ext1 gene has a high level of sequence similarity with its human homolog.
Ludecke et al. (1997) reported that the EXT1 gene contains 11 exons.
Ahn et al. (1995) identified the EXT1 gene within the breakpoint regions of chromosome 8q identified in patients with multiple exostoses type I. Lohmann et al. (1997) found that the murine Ext1 gene is part of a conserved linkage group on mouse chromosome 15.
Ahn et al. (1995) suggested that EXT1 may act as a tumor suppressor gene. Hecht et al. (1995) and Raskind et al. (1995) presented evidence suggesting that the EXT1 gene on chromosome 8 and the EXT2 gene (608210) on chromosome 11 have tumor suppressor function. They found loss of heterozygosity (LOH) for markers linked to these 2 genes in chondrosarcomas originating in individuals with multiple exostoses (see 133700) as well as in sporadic chondrosarcomas. The proteins encoded by the EXT1 and EXT2 genes play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. To explain the fact that normal bone growth occurs concurrently with abnormal exostosis tumor growth, Hecht et al. (1995) and Raskind et al. (1995) proposed a 2-hit tumor formation model according to the Knudson hypothesis (Knudson, 1971). In this model, a single germline mutation results in the predisposition for disease and a second somatic mutational hit, usually LOH, allows for aberrant growth. Hecht et al. (1997) noted that although the EXT1 protein is ubiquitously expressed in many tissues, the only known effect of mutated or inactivated EXT1 appears to be specific to actively growing bone, allowing inappropriate bone growth to be juxtaposed to the growth plate; as the bone continues to grow, the exostoses appear to migrate toward the diaphysis. At puberty, with growth plate fusion, linear growth ceases and no new exostoses develop.
McCormick et al. (1998) showed that EXT1 is an endoplasmic reticulum (ER)-resident type II transmembrane glycoprotein whose expression in cells results in the alteration of the synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs). Two EXT1 variants containing missense mutations related to multiple exostoses failed to alter cell surface glycosaminoglycans, despite retaining their ER localization. By testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, McCormick et al. (2000) showed that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1. Instead, it appears that EXT1 and EXT2 form a heterooligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone, suggesting that the complex represents the biologically relevant form of the enzyme(s). These findings provided a rationale for the causation of hereditary multiple exostoses by loss of activity in either of the 2 EXT genes.
Bovee et al. (1999) conducted studies to determine whether inactivation of both alleles of an EXT gene, according to the tumor suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a single dominant-negative way. They studied LOH and DNA ploidy in 8 sporadic and 6 hereditary osteochondromas. EXT1 and EXT2 mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. They demonstrated that osteochondroma is a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. The 2 patients with multiple osteochondromas demonstrated a germline mutation combined with the loss of the remaining wildtype allele in 3 osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene was required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations in the EXT2 gene were found in any of these cases.
Ropero et al. (2004) reported that EXT1 function was abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Epigenetic inactivation of EXT1 led to loss of heparan sulfate (HS) synthesis that was reversed by a DNA demethylating agent. Reintroduction of EXT1 into EXT1 methylation-deficient cancer cells induced tumor suppressor-like features, including reduced colony formation density and tumor growth in nude mouse xenograft models. By screening 79 human cancer cell lines and 454 primary tumors from different cell types, the authors found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and nonmelanoma skin cancer. Ropero et al. (2004) concluded that EXT1 epigenetic inactivation, leading to abrogation of HS biosynthesis, is an important step in the processes of tumor onset and progression.
Multiple Exostoses Type I
In 2 of 23 unrelated families with multiple exostoses type I (EXT1; 133700), Ahn et al. (1995) identified a 1-bp deletion in the EXT1 gene (608177.0001) that segregated with the disease. In 4 of 6 EXT families demonstrating linkage to the EXT1 locus on chromosome 8, Hecht et al. (1997) identified 3 germline mutations in the EXT1 gene that segregated with the disease phenotype in each family (608177.0002-608177.0004).
In 7 of 17 families (41%) with EXT, Philippe et al. (1997) identified mutations in the EXT1 gene, including 5 novel mutations (see, e.g., 608177.0007 and 608177.0009). Five of the families (29%) had mutations in the EXT2 gene. Wells et al. (1997) identified 6 mutations in the EXT1 gene in 6 unrelated EXT families showing linkage to chromosome 8. One of the mutations was the same 1-bp deletion in exon 6 that was previously reported in 2 independent EXT families (608177.0001). The other 5 mutations were novel. In each case, the mutation was predicted to result in a truncated or nonfunctional EXT1 protein.
Wuyts et al. (1998) analyzed the EXT1 and EXT2 genes in 26 EXT families originating from 9 countries. Of the 26 families, 10 had an EXT1 mutation and 10 had an EXT2 mutation. Twelve of these mutations had not previously been described. From a review of these and previously reported mutations, Wuyts et al. (1998) concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these 2 genes cause premature termination of the EXT proteins, whereas missense mutations are rare. The authors concluded that the development of exostoses is mainly due to loss of function of EXT genes, consistent with the hypothesis that the EXT genes have a tumor suppressor function.
Among 11 isolated cases of exostoses and 20 families with EXT, Raskind et al. (1998) identified 12 novel EXT1 mutations, including 5 frameshift deletions or insertions, 1 codon deletion, and 6 single basepair substitutions, distributed across 8 of the exons. Only 2 of the mutations were identified in more than 1 family. Three mutations affected sites in which alterations were previously reported. Nonchain-terminating missense mutations were identified in codons 280 and 340, both coding for conserved arginine residues. Raskind et al. (1998) suggested that these residues may be crucial to the function of this protein. One of the mutations (608177.0008) was identified in a Chamorro native on Guam, where EXT is unusually frequent. They concluded that 45% of the isolated cases and 77% of the familial cases could be attributed to abnormalities in EXT1.
In 23 of 43 Japanese families with hereditary multiple exostoses, Seki et al. (2001) found 21 mutations, of which 18 were novel. Seventeen (40%) of the 23 families had a mutation in the EXT1 gene and 6 (14%) had a mutation in the EXT2 gene. Of the 17 families with EXT1 mutations, 13 had those causing premature termination of the EXT1 protein, and 4 showed missense mutations. All 4 EXT1 missense mutations occurred in the arginine residue at codon 340 (R340L; 608177.0004). R340 is known as a critical site for expression of heparan sulfate glycosaminoglycans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein. In contrast to the findings of Seki et al. (2001), Xu et al. (1999) detected more mutations in EXT2 than in EXT1 in Chinese patients (33% and 14%, respectively). An excess of EXT1 mutations was found in Caucasian patients, however, by Philippe et al. (1997) and Wuyts et al. (1998). In both Caucasian patients, as studied by Raskind et al. (1998), and Japanese patients, more EXT1 mutations were identified in familial cases than in sporadic cases.
In a study of 82 Japanese patients with hereditary multiple exostoses by Seki et al. (2001), 4 patients developed malignancy and their mutations (3 in EXT1 and 1 in EXT2) were all different, suggesting that malignant transformation is not directly related to a particular mutation in EXT1 or EXT2, but more likely involves other genetic factors. Loss of heterozygosity has been detected in chondrosarcoma not only at the EXT loci but also at others such as 10q (RET; 164761) and 3q.
Wuyts and Van Hul (2000) stated that 49 different EXT1 and 25 different EXT2 mutations had been identified in patients with multiple exostoses and that mutations in these 2 genes were responsible for over 70% of the EXT cases. Most of the mutations cause loss of function, which is consistent with the presumed tumor suppressor function of the EXT genes.
McCormick et al. (1998) showed that the missense mutations G339D (608177.0007) and R340C (608177.0009) abrogate the ability of exostosin-1 to synthesize heparan sulfate (HS). Cheung et al. (2001) used a functional assay that detects HS expression on the cell surface of an EXT1-deficient cell line to test other missense mutant exostosin proteins for their ability to rescue HS biosynthesis in vivo. Their results showed that EXT1 mutants bearing 6 of these missense mutations are also defective in HS expression, but surprisingly, 4 missense mutations that had been considered etiologic were phenotypically indistinguishable from wildtype EXT1. Three of these 4 'active' mutations affect amino acids that are not conserved among vertebrates and invertebrates, whereas all of the HS-biosynthesis null mutations affect only conserved amino acids. Further, substitution or deletion of each of these 4 residues does not abrogate HS biosynthesis. Taken together, these results indicated that several of the reported etiologic mutant EXT forms retain the ability to synthesize and express HS on the cell surface. Cheung et al. (2001) suggested that these mutations may represent rare genetic polymorphisms in the EXT1 gene or may interfere with functions of EXT1 that are involved in the pathogenesis of hereditary multiple exostoses.
Hall et al. (2002) reported the direct sequencing and LOH analysis of 12 exostoses in 10 hereditary multiple exostoses families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, there was only 1 isolated case in which 2 somatic mutations, a deletion and an LOH, were present. Hall et al. (2002) developed alternative models of pathogenesis, including a second mutational event in genes other than EXT1 and EXT2, such as the EXTL1 (601738), EXTL2 (602411), and EXTL3 (605744) genes. Xu et al. (1999) found no germline mutations in the EXTL1 and EXTL2 genes of patients with hereditary multiple exostoses.
In 11 of 23 German patients with multiple exostoses, Heinritz et al. (2009) identified 11 different novel mutations in the EXT1 gene (see, e.g., 608177.0012). Eleven patients had mutations in the EXT2 gene, and 1 patient had no detectable mutations.
In 79 unrelated Italian patients with multiple exostoses type I, Fusco et al. (2019) identified 62 different heterozygous mutations in the EXT1 gene, of which 36 were novel. The mutations were identified by direct sequencing or by MLPA analysis followed by confirmation with quantitative real-time PCR. The mutations included 23 frameshifts, 22 nonsense, 6 missense, 9 splicing, and 2 intragenic rearrangements. The most common mutation was R340H (608177.0013), which occurred in 5 families. To evaluate the functional importance of EXT1 domains, Fusco et al. (2019) tested the effects of 2 mutations with a premature termination (C355X and Leu427ArgfsTer14), comprising the N-terminal exostosin domain or the C-terminal glycosyltransferase family 64 domain, in U2OS cells. The mutated proteins had abnormal localization patterns. These mutant EXT1 proteins were also expressed in HEK293 cells, which showed slower growth compared to cells expressing wildtype EXT1.
Chondrosarcoma
In a patient (individual 6) with chondrosarcoma (215300), Hecht et al. (1997) identified an EXT1 mutation in the constitutional DNA (608177.0005), but the tumor tissue had retained the wildtype allele. In a patient (individual 10) with sporadic chondrosarcoma, Hecht et al. (1997) identified a mutation in the tumor tissue (608177.0006), which was not present in the constitutional DNA.
Trichorhinophalangeal Syndrome Type II
Exostoses in the contiguous gene syndrome trichorhinophalangeal syndrome type II (150230) are caused by loss of functional copies of the EXT1 gene (Ludecke et al., 1995).
To define the developmental role of heparan sulfate in mammalian species, Inatani et al. (2003) conditionally disrupted the heparan sulfate polymerizing enzyme Ext1 in the embryonic mouse brain. The Ext1-null brain exhibited patterning defects that were composites of those caused by mutations of multiple heparan sulfate-binding morphogens. Furthermore, the Ext1-null brain displayed severe guidance errors in major commissural tracts, revealing a pivotal role of heparan sulfate in midline axon guidance. Inatani et al. (2003) concluded that heparan sulfate is essential for mammalian brain development.
By introducing a hypomorphic mutation in the Ext1 gene, Koziel et al. (2004) developed mice producing significantly reduced levels of heparan sulfate. Homozygous mutant embryos survived until embryonic day 14.5 at a nonmendelian ratio of 14%. Only 4% were recovered at embryonic day 16.5. Mutant embryos were small and edematous. They had heart defects, reduced skeleton size with fused vertebrae, shortened fore- and hindlimbs, fused elbow and knee joints, and occasionally syndactylies of digits. Homozygous mutant mice showed an extended distribution of Ihh (600726) signaling during embryonic chondrocyte differentiation, and ectopic heparan sulfate restricted Ihh signaling. The authors concluded that heparan sulfate binds hedgehog in the extracellular space and negatively regulates the range of hedgehog signaling in a dose-dependent manner.
Matsumoto et al. (2010) created a line of mice with random deletion of Ext1 in a small fraction of chondrocytes. Mutant mice developed osteochondromas of the wrist, fibula, shoulder, and rib. A high proportion of mutant animals also showed bowing deformity of the radius, subluxation/dislocation of the radial head, scoliosis, and mild abnormalities in the growth plate and joint cartilage. Genotyping showed that osteochondromas contained a high proportion of wildtype chondrocytes, in addition to Est1-null chondrocytes. The pattern of gene expression in osteochondromas more resembled that of ectopic growth plates than of neoplasms. Matsumoto et al. (2010) hypothesized that Est1-null chondrocytes are required for initiation of osteochondromas, but the subsequent growth of osteochondromas is not directly due to upregulated proliferation of mutant cells.
In 2 of 23 unrelated families with multiple exostoses type I (EXT1; 133700), Ahn et al. (1995) identified a 1-bp deletion (2120T) in the EXT1 gene, resulting in a premature stop codon. The mutation cosegregated with the disease in the families over 2 and 3 generations, respectively.
In 2 unrelated families with multiple exostoses type I (EXT1; 133700), Hecht et al. (1997) identified a 1-bp deletion (1364delC) in exon 1 of the EXT1 gene, resulting in a premature stop codon at nucleotide 1403.
In a family with multiple exostoses type I (EXT1; 133700), Hecht et al. (1997) identified a 4-bp insertion (1035ins4) in exon 1 of the EXT1 gene, resulting in a premature stop codon at nucleotide 1213.
In a family with multiple exostoses type I (EXT1; 133700), Hecht et al. (1997) identified a 1635G-T transversion in exon 2 of the EXT1 gene, resulting in an arg339-to-leu (R339L) substitution. It was subsequently discovered that the mutation was a 1670G-T transversion that resulted in an arg340-to-leu (R340L) substitution (Hogue, 1998).
In a patient with chondrosarcoma (215300), Hecht et al. (1997) identified a 1-bp insertion (2077-2082insC) in the EXT1 gene in the patient's constitutional DNA, resulting in a frameshift and a premature stop codon at nucleotide 2208 in exon 6. Interestingly, the tumor tissue retained the wildtype allele, but had LOH for chromosome 3q.
In the tumor tissue of a patient (individual 10) with sporadic chondrosarcoma (215300), Hecht et al. (1997) identified an 8-bp deletion (1178del8) in the EXT1 gene, resulting in a premature stop codon at nucleotide 1213. This mutation did not appear in the patient's constitutional DNA, suggesting somatic origin.
In a family with multiple exostoses type I (EXT1; 133700), Philippe et al. (1997) identified a gly339-to-asp (G339D) missense mutation in exon 2 of the EXT1 gene.
McCormick et al. (1998) showed that the G339D missense mutation abrogates heparan sulfate biosynthesis.
In a Chamorro native on Guam, Raskind et al. (1998) demonstrated that multiple exostoses were associated with a 108C-A transversion in exon 1 of the EXT1 gene, leading to a stop codon, tyr119-to-ter (Y119X). Raskind et al. (1998) suggested that identification of the Chamorro mutation could allow investigation of a possible founder effect in this population, which has an unusually high frequency of EXT.
In a family with multiple exostoses type I (EXT1; 133700), Philippe et al. (1997) identified an arg340-to-cys (R340C) mutation in exon 2 of the EXT1 gene.
McCormick et al. (1998) showed that the R340C missense mutation abrogates heparan sulfate biosynthesis.
In affected members of a large consanguineous Pakistani family with multiple exostoses type I (EXT1; 133700), Faiyaz-Ul-Haque et al. (2004) identified a G-to-C transversion at the conserved splice donor site in intron 1 of the EXT1 gene, predicted to result in a null allele. All affected individuals, and no unaffected individuals, had bilateral overriding of the fourth toe. This feature was present at birth, allowing earlier diagnosis of the disorder.
In affected members of a large consanguineous Pakistani family with multiple exostoses type I (EXT1; 133700), Faiyaz-Ul-Haque et al. (2004) identified a 1-bp insertion (1664insA) in exon 8 of the EXT1 gene, predicted to produce a frameshift at codon 555 resulting in a premature termination 10 codons downstream. Bilateral overriding of the second or third toes was observed in all affected individuals except for 1 asymptomatic female and 1 mildly affected female. No unaffected individuals had this feature, which was present at birth and allowed earlier diagnosis of the disorder.
In a German patient with multiple exostoses type I (EXT1; 133700), Heinritz et al. (2009) identified a heterozygous 4-bp deletion (962+1-962+4del4) in the 5-prime splice donor site of intron 1 of the EXT1 gene. The mutation results in the skipping of exon 2 and a frameshift with premature termination.
In 5 unrelated Italian patients with multiple exostoses type I (EXT1; 133700), Fusco et al. (2019) identified a heterozygous c.1019G-A transition (c.1019G-A, NM_000127.2) in exon 2 of the EXT1 gene, resulting in an arg340-to-his (R340H) substitution. The mutation was identified by direct sequencing of the EXT1 gene. Functional studies were not performed.
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