Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.5 (RNase)
 17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary familial and congenital polycythemia (PFCP) is an inherited disorder of erythroid progenitor cells resulting in elevated erythrocyte mass. Several mutations of the erythropoietin receptor (EPOR) gene have been associated with PFCP, although in a few families the linkage between the EPOR gene and PFCP has been excluded. To examine the role of EPOR mutations in the pathogenesis of PFCP, we studied 43 unrelated PFCP subjects. Erythroid culture data were available in 26 subjects, and in all these subjects, we observed hypersensitivity of erythroid progenitors to erythropoietin (EPO). We screened all EPOR gene exons for mutations using ribonuclease cleavage assay and protein truncation test. We detected five mutations in exon VIII of the EPOR gene, four of which we reported earlier. A new EPOR gene mutation was found (G5959T) that changes codon 425 GAG to a termination codon, resulting in truncation of the EPOR by 84 amino acids. The G5959T mutation was found to segregate with the disease in the affected family and represents another example of a nonsense mutation associated with PFCP. We also report the first intronic mutation (A2706T) of the EPOR gene. The finding of only five disease-causing mutations in our PFCP patient pool of 43 subjects (12%) indicates that EPOR gene mutations are not the major genetic defect associated with PFCP. The hypersensitivity of erythroid progenitors to EPO seen in all examined PFCP subjects suggests a dominant lesion of an as yet unidentified gene either at the level of the EPOR signaling pathway or another erythropoiesis regulating pathway.
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PMID:Genetic heterogeneity of primary familial and congenital polycythemia. 1155 51

Signalling by erythropoietin (EPO) is increasingly recognised as a relevant mechanism in tumour biology, potentially leading to enhanced proliferation, angiogenesis and therapy resistance. Paraneoplastic polycythemia by cancerous overproduction of EPO is a rare event, but most frequently seen in patients with renal cell carcinoma (RCC). The majority of clear cell RCC displays a strong activation of the transcription factor regulating EPO, the Hypoxia-inducible Factor (HIF). Therefore, it is unclear why only a small minority of patients develop polycythemia. We studied 70 RCC for EPO gene and HIFalpha isoform expression. 34% of all RCC showed expression of EPO mRNA in RNase protection assays, which were almost exclusively of the clear cell type. Only 1 patient presented with polycythemia. In situ hybridisation revealed that expression of EPO was in the tumour cells. Expression of EPO mRNA was always associated with activation of HIF, which could involve HIF-1alpha and/or HIF-2alpha. The frequency of EPO gene expression in RCC is therefore much higher than the prevalence of polycythemia. Furthermore, activation of HIF appears necessary for EPO gene expression in RCC, but is clearly not the only determinant. Further to the reported expression of EPO receptors in tumour tissues, the finding of widespread expression of EPO in RCC supports the recent notion of an involvement of this system in paracrine or autocrine effects of tumour cells.
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PMID:Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia. 1764 59