Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas

Sarrión, Patricia; Sangorrin, Anna; Urreizti, Roser; Delgado, María Andrea; Artuch, Rafael; Martorell, Loreto; Armstrong, Judith; Antón, Jordi; Torner, Ferrán; Vilaseca, M. A.; Nevado, Julián; Lapunzina, Pablo; Asteggiano, Carla; Balcells, Susana; Grinberg, Daniel

doi:10.1038/srep01346

Cited by 44 publications

(43 citation statements)

References 32 publications

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“…As previously reported in distinct populations (Ciavarella et al., ; Delgado et al.,; Heinritz et al., ; Ishimaru et al., ; Pedrini et al., ; Sarrión et al., ) a high number of novel pathogenic variants was also identified in Brazilian patients. Of all 50 different variants found in this study, 31 (62%) were novel with no description in the Multiple Osteochondroma Mutation Database (MOdb) (http://medgen.ua.ac.be/LOVDDv.2.0/home.php).…”

Section: Discussionsupporting

confidence: 75%

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Santos

Rizzo

Takata

et al. 2018

Molec Gen & Gen Med

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BackgroundMultiple 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.ResultsGermline 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.ConclusionThe 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.

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Section: Discussionsupporting

confidence: 75%

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Santos

Rizzo

Takata

et al. 2018

Molec Gen & Gen Med

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“…Mutations in the EXT1 and EXT2 genes were observed in Spanish patients with multiple osteochondromas. 26 Interestingly, our study also showed that EXT1 occurred in both SNPs and CNVs in OS, which suggested that EXT1 will be an important driver gene for the development of OS.…”

Section: Discussionmentioning

confidence: 87%

Integrated analysis of gene expression and genomic aberration data in osteosarcoma (OS)

Xiong

et al. 2015

Cancer Gene Ther

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Cytogenetic analyses have revealed that complex karyotypes with numerous and highly variable genomic aberrations including single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs), are observed in most of the conventional osteosarcomas (OSs). Several genome-wide studies have reported that the dysregulated expression of many genes is correlated with genomic aberrations in OS. We first compared OS gene expression in Gene Expression Omnibus (GEO) data sets and genomic aberrations in International Cancer Genome Consortium (ICGC) database to identify differentially expressed genes (DEGs) associated with SNPs or CNVs in OS. Then the function annotation of SNP- or CNV-associated DEGs was performed in terms of gene ontology analysis, pathway analysis and protein-protein interactions (PPIs). Finally, the expression of genes correlated with both SNPs and CNVs were confirmed by quantitative reverse-transcription PCR. Eight publicly available GEO data sets were obtained, and a set of 979 DEGs were identified (472 upregulated and 507 downregulated DEGs). Moreover, we obtained 1039 SNPs mapped in 938 genes, and 583 CNV sites mapped in 2915 genes. Comparing genomic aberrations and DGEs, we found 41 SNP-associated DEGs and 124 CNV-associated DEGs, in which 7 DGEs were associated with both SNPs and CNVs, including WWP1, EXT1, LDHB, C8orf59, PLEKHA5, CCT3 and VWF. The result of function annotation showed that ossification, bone development and skeletal system development were the significantly enriched terms of biological processes for DEGs. PPI network analysis showed that CCT3, COPS3 and WWP1 were the significant hub proteins. We conclude that these genes, including CCT3, COPS3 and WWP1 are candidate driver genes of importance in OS tumorigenesis.

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“…Primer sequences and PCR conditions were as described by Sarrión et al 201342. All fragments, except those corresponding to exon 1 of EXT1 , could be amplified by PCR simultaneously.…”

Section: Methodsmentioning

confidence: 99%

A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG

Delgado

Martinez-Domenech

Sarrión

et al. 2014

Sci Rep

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Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG.

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Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas

Cited by 44 publications

References 32 publications

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas

Integrated analysis of gene expression and genomic aberration data in osteosarcoma (OS)

A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG

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