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1.
Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by benign bone tumors. In this report, we describe two unrelated Chinese families with HME. Linkage analysis and mutation detection was performed. Clinical analysis was also performed for some affected individual in both families. Linkage with the EXT2 was established in both families. A novel mutation, c505 G > T, was identified in both families. Further allelic heterogeneity of EXT2 was demonstrated by the intrafamilial and interfamilial variability in clinical phenotype. 相似文献
2.
Sfar S Abid A Mahfoudh W Ouragini H Ouechtati F Abdelhak S Chouchane L 《Molecular biology reports》2009,36(4):661-667
Hereditary multiple exostoses (HME) is an autosomal dominant orthopaedic disorder most frequently caused by mutations in the
EXT1 gene. The aim of the present study is to determine the underlying molecular defect of HME in two multigenerational Tunisian
families with 21 affected members and to examine the degree of intrafamilial variability. Linkage analysis was performed using
three microsatellite markers encompassing the EXT1 locus and mutation screening was carried out by direct sequencing. In family 1, evidence for linkage to EXT1 was obtained on the basis of a maximum LOD score of 4.26 at θ = 0.00 with D8S1694 marker. Sequencing of the EXT1 revealed a heterozygous G > T transversion (c.1019G>T) in exon 2, leading to a missense mutation at the codon 340 (p.Arg340Leu).
In family 2 we identified a novel heterozygous 1 bp deletion in the exon 1 (c.529_531delA) leading to a premature codon stop
and truncated EXT1 protein expression (p.Lys177LysfsX15). This mutation was associated with the evidence of an intrafamilial
clinical variability and considered to be a novel disease-causing mutation in the EXT1 gene. These findings provide additional support for the involvement of EXT1 gene in the HME disease. 相似文献
3.
4.
Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by growth of benign bone tumors. This genetically heterozygous disease comprises three chromosomal loci: the EXT1 gene on chromosome 8q23-q24, EXT2 on 11p11-p13, and EXT3 on 19p. Both EXT1 and EXT2 have been cloned and defined as a new family of potential tumor suppressor genes in previous work. However, no studies have been conducted in the Taiwanese population. To determine if previous results can also be applied to the Taiwanese, we analyzed 5 Taiwanese probands with clinical features of HME: 1 of them is a sporadic case, and the others are familial cases. Linkage studies were performed in the familial cases before the mutation analysis to determine to which of the three EXT chromosomes these cases could be assigned. Our results showed that one proband is linked to the EXT1 locus and three are linked to the EXT2 locus; the sporadic case was subsequently found to involve EXT1. We then identified four new mutations that have not been found in other races: two in EXT1--frameshift (K218fsX247) and nonsense (Y468X) mutations and two in EXT2-missense (R223P) and nonsense (Y394X) mutations. Our results indicate that in familial cases, linkage analysis can prove useful for preimplantation genetic diagnosis. 相似文献
5.
Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. 总被引:4,自引:0,他引:4
C Philippe D E Porter M E Emerton D E Wells A H Simpson A P Monaco 《American journal of human genetics》1997,61(3):520-528
Hereditary multiple exostoses (HME), the most frequent of all skeletal dysplasias, is an autosomal dominant disorder characterized by the presence of multiple exostoses localized mainly at the end of long bones. HME is genetically heterogeneous, with at least three loci, on 8q24.1 (EXT1), 11p11-p13 (EXT2), and 19p (EXT3). Both the EXT1 and EXT2 genes have been cloned recently and define a new family of potential tumor suppressor genes. This is the first study in which mutation screening has been performed for both the EXT1 and EXT2 genes prior to any linkage analysis. We have screened 17 probands with the HME phenotype, for alterations in all translated exons and flanking intronic sequences, in the EXT1 and EXT2 genes, by conformation-sensitive gel electrophoresis. We found the disease-causing mutation in 12 families (70%), 7 (41%) of which have EXT1 mutations and 5 (29%) EXT2 mutations. Together with the previously described 1-bp deletion in exon 6, which is present in 2 of our families, we report five new mutations in EXT1. Two are missense mutations in exon 2 (G339D and R340C), and the other three alterations (a nonsense mutation, a frameshift, and a splicing mutation) are likely to result in truncated nonfunctional proteins. Four new mutations are described in EXT2. A missense mutation (D227N) was found in 2 different families; the other three alterations (two nonsense mutations and one frameshift mutation) lead directly or indirectly to premature stop codons. The missense mutations in EXT1 and EXT2 may pinpoint crucial domains in both proteins and therefore give clues for the understanding of the pathophysiology of this skeletal disorder. 相似文献
6.
Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus 总被引:4,自引:0,他引:4
Kobayashi S Morimoto K Shimizu T Takahashi M Kurosawa H Shirasawa T 《Biochemical and biophysical research communications》2000,268(3):860-867
We prepared the specific antibodies for EXT1 and EXT2, hereditary multiple exostoses (HME) gene products, and characterized their expression, subcellular localization, and protein association among EXT members. Biochemical analyses indicate that EXT1 and EXT2 can associate and form homo/hetero-oligomers in vivo with or without HME-linked mutations, EXT1 (R340C) and EXT2 (D227N), when exogenously expressed in COS-7 cells. An immunocytochemical analysis showed that both EXT1 and EXT2 localized in Golgi apparatus, irrespective of HME mutations. An immunohistochemical analysis on developing bones further showed that both EXT1 and EXT2 were concomitantly expressed in hypertrophic chondrocytes of forelimb bones from 1-day-old neonatal mouse, but down-regulated in maturing chondrocytes of developing cartilage from 21-day-old mouse. Taken together with the recent finding that EXTs encode for the glycosyltransferase required for the synthesis of heparan sulfate [Lind, T., Tufaro, F., McCormick, C., Lindahl, U., and Lindholt, K. (1998) J. Biol. Chem. 273, 26265-26268], our results implied a molecular basis that a HME-linked mutation found in EXT genes could interfere the physiological function(s) of EXT homo/hetero-oligomers as glycosyltransferases in the developing bones of HME patients. 相似文献
7.
Hereditary multiple exostoses and heparan sulfate polymerization 总被引:3,自引:0,他引:3
Hereditary multiple exostoses (HME, OMIM 133700, 133701) results from mutations in EXT1 and EXT2, genes encoding the copolymerase responsible for heparan sulfate (HS) biosynthesis. Members of this multigene family share the ability to transfer N-acetylglucosamine to a variety of oligosaccharide acceptors. EXT1 and EXT2 encode the copolymerase, whereas the roles of the other EXT family members (EXTL1, L2, and L3) are less clearly defined. Here, we provide an overview of HME, the EXT family of proteins, and possible models for the relationship of altered HS biosynthesis to the ectopic bone growth characteristic of the disease. 相似文献
8.
Aleksander Jamsheer Magdalena Socha Anna Sowińska-Seidler Kinga Telega Tomasz Trzeciak Anna Latos-Bieleńska 《Journal of applied genetics》2014,55(2):183-188
Hereditary multiple exostoses (HME) also known as multiple osteochondromas represent one of the most frequent bone tumor disorder in humans. Its clinical presentation is characterized by the presence of multiple benign cartilage-capped tumors located most commonly in the juxta-epiphyseal portions of long bones. HME are usually inherited in autosomal dominant manner, however de novo mutations can also occur. In most patients, the disease is caused by alterations in the EXT1 and EXT2 genes. In this study we investigated 33 unrelated Polish probands with the clinical and radiological diagnosis of HME by means of Sanger sequencing and MLPA for all coding exons of EXT1 and EXT2. We demonstrated EXT1 and EXT2 heterozygous mutations in 18 (54.6 %) and ten (30.3 %) probands respectively, which represents a total of 28 (84.9 %) index cases. Sequencing allowed for the detection of causative changes in 26 (78.8 %) probands, whereas MLPA showed intragenic deletions in two (6.1 %) further cases (15 mutations represented novel changes). Our paper is the first report on the results of exhaustive mutational screening of both EXT1/EXT2 genes in Polish patients. The proportion of EXT1/EXT2 mutations in our group was similar to other Caucasian cohorts. However, we found that EXT1 lesions in Polish patients cluster in exons 1 and 2 (55.6 % of all EXT1 mutations). This important finding should lead to the optimization of cost-effectiveness rate of HME diagnostic testing. Therefore, the diagnostic algorithm for HME should include EXT1 sequencing (starting with exons 1–2), followed by EXT2 sequencing, and MLPA/qPCR for intragenic copy number changes. 相似文献
9.
Transgenic expression of the EXT2 gene in developing chondrocytes enhances the synthesis of heparan sulfate and bone formation in mice 总被引:1,自引:0,他引:1
Morimoto K Shimizu T Furukawa K Morio H Kurosawa H Shirasawa T 《Biochemical and biophysical research communications》2002,292(4):999-1009
Hereditary multiple exostoses (HME), a dominantly inherited disorder characterized by multiple cartilaginous tumors, is caused by mutations in the gene for, EXT1 or EXT2. Recent studies have revealed that EXT1 and EXT2 are required for the biosynthesis of heparan sulfate and exert maximal transferase activity as a complex. The Drosophila homologue of EXT1 (tout-velu) regulates the movement and signaling of Hedgehog protein, which plays an important role in the regulation of chondrocyte differentiation and bone development. In this study, to investigate the biological role of EXT2 in bone development in vivo and the pathological role of HME mutations in the development of exostoses, we generated transgenic mice expressing EXT2 or mutant EXT2 in developing chondrocytes. Histological analyses and micro-CT scanning showed that the biosynthesis of heparan sulfate and the formation of trabeculae were upregulated in EXT2-transgenic mice, but not in mutant EXT2-transgenic mice. The expression of EXT1 is concomitantly upregulated in EXT2-transgenic and even mutant EXT2-transgenic mice, suggesting an interactive regulation of EXT1 and EXT2 expression. These findings support that the EXT2 gene encodes an essential component of the glycosyltransferase complex required for the biosynthesis of heparan sulfate, which may eventually modulate the signaling involved in bone formation. 相似文献
10.
Bone development is a highly regulated process sensitive to a wide variety of hormones, inflammatory mediators and growth factors. One of the most common hereditary skeletal dysplasias, hereditary multiple exostoses (HME), is an autosomal dominant disorder characterized by skeletal malformations that manifest as bony, benign tumours near the end of long bones. HME is usually caused by defects in either one of two genes, EXT1 and EXT2, which encode enzymes that catalyse the biosynthesis of heparan sulphate, an important component of the extracellular matrix. Thus, HME-linked bone tumours, like many other skeletal dysplasias, probably result from disruptions in cell surface architecture. However, despite the recent success in unravelling functions for several members of the EXT gene family, significant challenges remain before this knowledge can be used to develop new approaches for the diagnosis and treatment of disease. 相似文献
11.
Bernard MA Hall CE Hogue DA Cole WG Scott A Snuggs MB Clines GA Lüdecke HJ Lovett M Van Winkle WB Hecht JT 《Cell motility and the cytoskeleton》2001,48(2):149-162
The EXT family of putative tumor suppressor genes affect endochondral bone growth, and mutations in EXT1 and EXT2 genes cause the autosomal dominant disorder Hereditary Multiple Exostoses (HME). Loss of heterozygosity (LOH) of these genes plays a role in the development of exostoses and chondrosarcomas. In this study, we characterized EXT genes in 11 exostosis chondrocyte strains using LOH and mutational analyses. We also determined subcellular localization and quantitation of EXT1 and EXT2 proteins by immunocytochemistry using antibodies raised against unique peptide epitopes. In an isolated non-HME exostosis, we detected three genetic hits: deletion of one EXT1 gene, a net 21-bp deletion within the other EXT1 gene and a deletion in intron 1 causing loss of gene product. Diminished levels of EXT1 and EXT2 protein were found in 9 (82%) and 5 (45%) exostosis chondrocyte strains, respectively, and 4 (36%) were deficient in levels of both proteins. Although we found mutations in exostosis chondrocytes, mutational analysis alone did not predict all the observed decreases in EXT gene products in exostosis chondrocytes, suggesting additional genetic mutations. Moreover, exostosis chondrocytes exhibit an unusual cellular phenotype characterized by abnormal actin bundles in the cytoplasm. These results suggest that multiple mutational steps are involved in exostosis development and that EXT genes play a role in cell signaling related to chondrocyte cytoskeleton regulation. 相似文献
12.
Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity 总被引:13,自引:0,他引:13
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Cheung PK McCormick C Crawford BE Esko JD Tufaro F Duncan G 《American journal of human genetics》2001,69(1):55-66
Hereditary multiple exostoses (HME), a dominantly inherited genetic disorder characterized by multiple cartilaginous tumors, is caused by mutations in members of the EXT gene family, EXT1 or EXT2. The corresponding gene products, exostosin-1 (EXT1) and exostosin-2 (EXT2), are type II transmembrane glycoproteins which form a Golgi-localized heterooligomeric complex that catalyzes the polymerization of heparan sulfate (HS). Although the majority of the etiological mutations in EXT are splice-site, frameshift, or nonsense mutations that result in premature termination, 12 missense mutations have also been identified. Furthermore, two of the reported etiological missense mutations (G339D and R340C) have been previously shown to abrogate HS biosynthesis (McCormick et al. 1998). Here, a functional assay that detects HS expression on the cell surface of an EXT1-deficient cell line was used to test the remaining missense mutant exostosin proteins for their ability to rescue HS biosynthesis in vivo. Our results show that EXT1 mutants bearing six of these missense mutations (D164H, R280G/S, and R340S/H/L) are also defective in HS expression, but surprisingly, four (Q27K, N316S, A486V, and P496L) are phenotypically indistinguishable from wild-type EXT1. Three of these four "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 four residues does not abrogate HS biosynthesis. Taken together, these results indicate that several of the reported etiological mutant EXT forms retain the ability to synthesize and express HS on the cell surface. The corresponding missense mutations may therefore represent rare genetic polymorphisms in the EXT1 gene or may interfere with as yet undefined functions of EXT1 that are involved in HME pathogenesis. 相似文献
13.
Sophie J. Bernelot Moens Hans L. Mooij H . Carlijne Hassing Janine K. Kruit Julia J. Witjes Michiel A. J. van de Sande Aart J. Nederveen Ding Xu Geesje M. Dallinga-Thie Jeffrey D. Esko Erik S. G. Stroes Max Nieuwdorp 《PloS one》2014,9(12)
Exotosin (EXT) proteins are involved in the chain elongation step of heparan sulfate (HS) biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF) in EXT1 and EXT2 result in hereditary exostoses (HME). Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME) affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT) followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS) in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI). OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46–1.16] vs. controls 1.53 [0.69–3.36] nmol·l−1·min−1, p<0.05). Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22–10.5] vs. controls 10.2 [7.91–12.70] nmol·l−1·min−1 p<0.05), indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04). In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors. 相似文献
14.
Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXT-linked markers on chromosomes II and 8. 总被引:5,自引:3,他引:2
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J T Hecht D Hogue L C Strong M F Hansen S H Blanton M Wagner 《American journal of human genetics》1995,56(5):1125-1131
Hereditary multiple exostosis (EXT) is an autosomal dominant disorder characterized by bony exostoses at the ends of the long bones. Linkage studies have recently suggested that there are three chromosomal locations for EXT genes, 8q24.1 (EXT1), the pericentric region of 11 (EXT2), and 19p (EXT3). As part of a larger study to determine the frequencies of the three EXT types in the United States, we have ascertained a large multigenerational family with EXT and one family member with a chondrosarcoma. This family demonstrated linkage of the disease to chromosome 11 markers. The constitutional and tumor DNAs from the affected family member were compared using short-tandem-repeat markers from chromosomes 8, 11, and 19. Loss of heterozygosity (LOH) in the tumor was observed for chromosome 8 and 11 markers, but chromosome 19 markers were intact. An apparent deletion of the marker D11S903 was observed in constitutional DNA from all affected individuals and in the tumor sample. These results indicate that the EXT2 gene maps to the region containing marker D11S903, which is flanked by markers D11S1355 and D11S1361. Additional constitutional and chondrosarcoma DNA pairs from six unrelated individuals, two of whom had EXT, were similarly analyzed. One tumor from an individual with EXT demonstrated LOH for chromosome 8 markers, and a person with a sporadic chondrosarcoma was found to have tumor-specific LOH and a homozygous deletion of chromosome 11 markers. These findings suggest that EXT genes may be tumor-suppressor genes and that the initiation of tumor development may follow a multistep model. 相似文献
15.
Multiple osteochondromas (MO; also referred to as hereditary multiple exostoses [HME] in the literature) is an autosomal dominant disorder characterized by benign, cartilage-capped bone tumors that grow from the metaphyses of long bones. Two genes are associated with this disease: EXT1 on 8q24.11-q24.13 and EXT2 on 11p12-p11. Mutations in EXT1 and EXT2 are found in 54-96% of patients with MO and are generally more frequent in EXT1 than in EXT2. We previously studied 43 Japanese families with MO using single-strand conformation polymorphism analysis for EXT1 and EXT2, and reported 23 families (54%) with mutations and 20 families (46%) with no mutations in these genes. Among the families with mutations, 17 families (40%) had mutations in EXT1, and 6 families (14%) had mutations in EXT2. Here we examined the same 43 Japanese families using denaturing high-performance liquid chromatography as an alternative technique. We detected five mutations, three of which are novel, in seven families in addition to the previously described mutations. In summary, we detected mutations in EXT1 or EXT2 in 30 (70%) out of 43 families. Our result suggests the presence of other gene(s) responsible for MO, at least in Japanese patients. 相似文献
16.
Leube B Hardt K Portier S Westhoff B Jäger M Krauspe R Royer-Pokora B 《Genetic testing》2008,12(1):129-133
Multiple osteochondromas (MO) is an autosomal-dominant inherited disorder. The two genes responsible (EXT1 and EXT2) have been identified. We investigated 12 MO families for phenotype details and the genetic basis by cosegregation and mutation analysis (seven novel pathogenic mutations [five frameshift, one splice site, and one gross deletion] and one novel missense polymorphism). We found EXT1 to be responsible in seven families (19 affected members) and EXT2 in four families (17 affected members). One family remains undetermined. We found a tendency to a more severe phenotype in EXT1 families. As a novel finding, we could identify a single parameter (ulna/height ratio) that separates EXT1 family from EXT2 family in our series. 相似文献
17.
Hecht JT Hayes E Haynes R Cole WG Long RJ Farach-Carson MC Carson DD 《Differentiation; research in biological diversity》2005,73(5):212-221
An exostosis or osteochondroma is an aberrant bony growth occurring next to the growth plate either as an isolated growth abnormality or as part of the Hereditary Multiple Exostosis (HME) syndrome. Mutations in either exostosin 1 (EXT1) or exostosin 2 (EXT2) gene cause the HME syndrome and also some isolated osteochondromas. The EXT1 and EXT2 genes are glycosyltransferases that function as hetero-oligomers in the Golgi to add repeating glycosaminoglycans (GAGs) to heparan sulfate (HS) chains. Previously, we demonstrated that HS is markedly diminished in the exostosis cartilage cap and that the HS proteoglycan, perlecan, has an abnormal distribution in these caps. The present studies were undertaken to evaluate which chondrocyte-specific functions are associated with diminished HS synthesis in human chondrocytes harboring either EXT1 or EXT2 mutations. Systematic evaluation of exostosis cartilage caps and chondrocytes, both in vitro and in vivo, suggests that chondrocyte-specific cell functions account for diminished HS levels. In addition, we provide evidence that perichondrial cells give rise to chondrocytes that clonally expand and develop into an exostosis. Undifferentiated EXT chondrocytes synthesized amounts of HS similar to control chondrocytes; however, EXT chondrocytes displayed very poor survival in vitro under conditions that promote normal chondrocyte differentiation with high efficiency. Collectively, these observations suggest that loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial chondrocytes' ability to differentiate normally and to survive in a differentiated state in vitro. In vivo, these compromised responses may lead to abnormal chondrocyte growth, perhaps from a perichondrial stem cell reserve. 相似文献
18.
Feng Zhang Jinlong Liang Xiong Guo Yingang Zhang Yan Wen Qiang Li Zengtie Zhang Weijuan Ma Lanlan Dai Xuanzhu Liu Ling Yang Jun Wang 《PloS one》2013,8(8)
Multiple osteochondromas (MO) is an inherited skeletal disorder, and the molecular mechanism of MO remains elusive. Exome sequencing has high chromosomal coverage and accuracy, and has recently been successfully used to identify pathogenic gene mutations. In this study, exome sequencing followed by Sanger sequencing validation was first used to screen gene mutations in two representative MO patients from a Chinese family. After filtering the data from the 1000 Genome Project and the dbSNP database (build 132), the detected candidate gene mutations were further validated via Sanger sequencing of four other members of the same MO family and 200 unrelated healthy subjects. Immunohistochemisty and multiple sequence alignment were performed to evaluate the importance of the identified causal mutation. A novel frameshift mutation, c.1457insG at codon 486 of exon 6 of EXT1 gene, was identified, which truncated the glycosyltransferase domain of EXT1 gene. Multiple sequence alignment showed that codon 486 of EXT1 gene was highly conserved across various vertebrates. Immunohistochemisty demonstrated that the chondrocytes with functional EXT1 in MO were less than those in extragenetic solitary chondromas. The novel c.1457insG deleterious mutation of EXT1 gene reported in this study expands the causal mutation spectrum of MO, and may be helpful for prenatal genetic screening and early diagnosis of MO. 相似文献
19.
W Wuyts W Van Hul K De Boulle J Hendrickx E Bakker F Vanhoenacker F Mollica H J Lüdecke B S Sayli U E Pazzaglia G Mortier B Hamel E U Conrad M Matsushita W H Raskind P J Willems 《American journal of human genetics》1998,62(2):346-354
Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function. 相似文献
20.
L. Xu J. Xia H. Jiang J. Zhou H. Li D. Wang Q. Pan Z. Long C. Fan H.-X. Deng 《Human genetics》1999,105(1-2):45-50
Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder. It is genetically heterogeneous with
at least three chromosomal loci: EXT1 on 8q24.1, EXT2 on 11p11, and EXT3 on 19p. EXT1 and EXT2, the two genes responsible for EXT1 and EXT2, respectively, have been cloned. Recently, three other members of the EXT gene
family, named the EXT-like genes (EXTL: EXTL1, EXTL2, and EXTL3), have been isolated. EXT1, EXT2, and the three EXTLs are homologous with one another. We have identified the intron-exon boundaries of EXTL1 and EXTL3 and analyzed EXT1, EXT2, EXTL1, and EXTL3, in 36 Chinese families with EXT, to identify underlying disease-related mutations in the Chinese population. Of the 36 families,
five and 12 family groups have mutations in EXT1 and EXT2, respectively. No disease-related mutation has been found in either EXTL1 or EXTL2, although one polymorphism has been detected in EXTL1. Of the 15 different mutations (three families share a common mutation in EXT2), 12 are novel. Most of the mutations are either frameshift or nonsense mutations (12/15). These mutations lead directly
or indirectly to premature stop codons, and the mutations generate truncated proteins. This finding is consistent with the
hypothesis that the development of EXT is mainly attributable to loss of gene function. Missense mutations are rare in our
families, but these mutations may reflect some functionally crucial regions of these proteins. EXT1 is the most frequent single cause of EXT in the Caucasian population in Europe and North America. It accounts for about 40%
of cases of EXT. Our study of 36 EXT Chinese families has found that EXT1 seems much less common in the Chinese population, although the frequency of the EXT2 mutation is similar in the Caucasian and Chinese populations. Our findings suggest a possibly different genetic spectrum
of this disease in different populations.
Electronic Publication 相似文献