Identification and functional characterization of the human EXT1 promoter region

Jennes, Ivy; Zuntini, Monia; Mees, Kirsten; Palagani, Ajay; Pedrini, Elena; Cock, G. De; Fransén, Erik; Berghe, Wim Vanden; Sangiorgi, Luca; Wuyts, Wim

doi:10.1016/j.gene.2011.10.034

Cited by 21 publications

(22 citation statements)

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“…We found that four patients (P18, P21, P34 and P41), and one control individual, were heterozygous carriers of the C allele of SNP rs34016643, which has been previously shown to have a significant effect on EXT1 promoter activity, with the C-allele resulting in a 56% rise in promoter activity compared to the G (wild–type) allele30. No pathogenic mutation was identified in EXT1 or EXT2 in three of these four patients, while patient P41 bore a nonsense mutation (c.1219C > T, p.Gln407*) in exon 4 of the EXT1 gene (Table 1).…”

Section: Resultsmentioning

confidence: 77%

“…We sequenced 435 bp upstream of the EXT1 gene including the 123-bp region described to contain the basic promoter elements30 in samples from patients and 9 controls, but no mutation was detected. We found that four patients (P18, P21, P34 and P41), and one control individual, were heterozygous carriers of the C allele of SNP rs34016643, which has been previously shown to have a significant effect on EXT1 promoter activity, with the C-allele resulting in a 56% rise in promoter activity compared to the G (wild–type) allele30.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, the promoter of EXT1 was analysed in some cases. The EXT1 core promoter region was reported to map to approximately −917 bp upstream of the EXT1 start codon, within a 123-bp region30. One SNP within this region, rs34016643, was shown to have a significant effect on EXT1 promoter activity (the C-allele resulting in a 56% rise in promoter activity) compared to the G-wild-type allele30.…”

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confidence: 99%

“…The EXT1 core promoter region was reported to map to approximately −917 bp upstream of the EXT1 start codon, within a 123-bp region30. One SNP within this region, rs34016643, was shown to have a significant effect on EXT1 promoter activity (the C-allele resulting in a 56% rise in promoter activity) compared to the G-wild-type allele30. The presence of an additional MO-causing gene has been proposed to explain the absence of an EXT1 or EXT2 mutation in a small percentage of MO patients (15–30%)173132.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…Since the cause of abnormal expression may be the polymorphism in the gene and some polymorphic variants can influence the gene expression (Jennes et al 2012;Li et al 2012), we further investigated the association between LAPTM5 tagSNPs (rs10798801, rs4614309, rs1188348, and rs1188349) and SLE in a Chinese population. The distribution of both allelic and genotypic frequencies of the LAPTM5 polymorphisms showed no significant association between the SLE patients and healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Expression and Polymorphisms of Lysosome-Associated Protein Transmembrane 5 (LAPTM5) in Patients with Systemic Lupus Erythematosus in a Chinese Population

et al. 2015

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Lysosome-associated protein transmembrane 5 (LAPTM5) have been demonstrated a role in the prevention of lymphocyte hyperactivation, and its deficiency is involved in the immunological dysfunction of mouse models. The aim of this study was to detect mRNA expression of LAPTM5 in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE), and to assess association between LAPTM5 single nucleotide polymorphisms (SNPs) (rs10798801, rs4614309, rs1188348, and rs1188349) and SLE in a Chinese population. Real-time transcription-polymerase chain reaction analysis was used to determine expression of LAPTM5 mRNA in PBMCs from 132 patients with SLE and 62 healthy controls. LAPTM5 mRNA expression decreased in SLE patients (n = 71) compared with healthy controls (n = 58) (p = 3.68 × 10(-5)). The expression of LAPTM5 mRNA in SLE patients with lupus nephritis (LN) (n = 35) was lower than in those without LN (n = 36) (p = 0.004). The expression level of LAPTM5 correlated with serum total protein (r(s) = 0.41, p = 0.027) and negatively correlated with 24-h proteinuria (r(s) = -0.45, p = 0.027). LAPTM5 SNPs (rs10798801, rs4614309, rs1188348, and rs1188349) was also analyzed by restriction fragment length polymorphism (RFLP) in 380 SLE patients and 460 healthy controls. No significant difference in the genotype or allele frequencies for LAPTM5 SNPs was detected in 380 SLE patients and 460 healthy controls (p > 0.05). Substantially low frequency of GGAT haplotype was observed in SLE patients (p < 0.001). It is concluded that insufficient expression of LAPTM5 may take part in the pathogenesis of SLE and contribute to the severity of the disease, and none of LAPTM5 polymorphisms contributes significantly to SLE susceptibility in a Chinese population.

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Molecular Genetics of Multiple Osteochondromas

Andrea

Hogendoorn

Bovée

2016

Encyclopedia of Life Sciences

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Multiple osteochondromas (MOs) is an autosomal dominant disease characterised by MOs (previously named exostoses). Their formation requires bi‐allelic inactivation of EXT1 or EXT2 genes in growth plate cartilage. They encode glycosyltransferases that catalyse the chain elongation step in heparan sulfate biosynthesis and when mutated cause a variety of growth factor signalling defects, impaired cell–matrix interactions and loss of polarity. Osteochondromas are not clonal neoplasms, but a mixed population of cells harbouring homozygous loss of either EXT genes or cells retaining the EXT wild‐type allele. About 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary chondrosarcoma. Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation, possibly by inactivation of the CDKN2A locus. This locus encodes INK4a (p16), which regulates RB1, and p19ARF, which regulates P53. Inactivation of CDKN2A by mutation or deletion is a common pathway for oncogenesis. Key Concepts Patients with MO are characterised genetically by germline mutations in EXT1 and EXT2 genes and phenotypically by the development of at least two osteochondromas. Osteochondroma is a benign cartilage‐capped bony projection arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone. Osteochondromas are the most frequent cartilaginous lesions, most often found on the femur (21%), humerus (17%) and tibia (11%). Somatic inactivation of both EXT alleles results in significantly shorter heparan sulfate chains. Defective heparan sulfate biosynthesis results in abnormal diffusion and signalling of IHH and FGFR3 causing increased proliferation and delayed differentiation. Approximately 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary peripheral chondrosarcoma. An osteochondroma cap exceeding 1.5–2 cm in adults is suggestive of malignancy. The most common location for malignant transformation of an osteochondroma is the pelvis, where large lesions can be difficult to excise completely. Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation. Secondary peripheral chondrosarcoma typically shows chromosome instability with gains and losses and genomic diversity that increases with increasing grade of malignancy. Loss of heterozygosity for the chromosomal bands bearing the RB1 and CDKN2A ( p16INK4a ) tumour suppressor genes is often found.

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Identification and functional characterization of the human EXT1 promoter region

Cited by 21 publications

References 53 publications

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

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

Expression and Polymorphisms of Lysosome-Associated Protein Transmembrane 5 (LAPTM5) in Patients with Systemic Lupus Erythematosus in a Chinese Population

Molecular Genetics of Multiple Osteochondromas

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