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Alain Gustave Zeimet - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Folate Receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers
BMC Cancer, 2016Co-Authors: Sara Notaro, Daniel Reimer, Heidi Fiegl, Gabriel Schmid, Annamarie Wiedemair, Julia Rössler, Christian Marth, Alain Gustave ZeimetAbstract:Background In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer. Methods Two hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique. Results No correlation between FOLR1 mRNA expression and its specific promoter DNA methylation was found neither in type I nor in type II cancers, however, high FOLR1 mRNA expression was found to be correlated with global DNA hypomethylation in type II cancers ( p = 0.033). Strong FOLR1 mRNA expression was revealed for Grades 2-3, FIGO stages III-IV, residual disease > 0, and serous histotype. High FOLR1 expression was found to predict increased platinum sensitivity in type I cancers (odds ratio = 3.288; 1.256-10.75; p = 0.020). One-year survival analysis showed in type I cancers an independent better outcome for strong expression of FOLR1 in FIGO stage III and IV. For the entire follow up period no significant independent outcome for FOLR1 expression was revealed. In type I cancers LINE 1 DNA hypomethylation was found to exhibit a worse PFS and OS which were confirmed to be independent in multivariate COX regression model for both PFS ( p = 0.026) and OS ( p = 0.012). Conclusion No correlations were found between FOLR1 expression and its specific promoter methylation, however, high FOLR1 mRNA expression was associated with DNA hypomethylation in type II cancers. FOLR1 mRNA expression did not prove to predict clinical outcome in type II cancers, although strong FOLR1 expression generally denotes ovarian cancers with highly aggressive phenotype. In type I cancers, however, strong FOLR1 expression has been found to be a reliable indicator of improved platinum responsiveness reflecting a transient better one-year follow up outcome in highly FOLR1 expressing type I cancers. An independent prognostic role of global DNA hypomethylation was demonstrated in type I tumours.
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evaluation of Folate Receptor 1 folr1 mrna expression its specific promoter methylation and global dna hypomethylation in type i and type ii ovarian cancers
BMC Cancer, 2016Co-Authors: Sara Notaro, Daniel Reimer, Heidi Fiegl, Gabriel Schmid, Annamarie Wiedemair, Julia Rössler, Christian Marth, Alain Gustave ZeimetAbstract:Background In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer.
Sara Notaro - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Folate Receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers
BMC Cancer, 2016Co-Authors: Sara Notaro, Daniel Reimer, Heidi Fiegl, Gabriel Schmid, Annamarie Wiedemair, Julia Rössler, Christian Marth, Alain Gustave ZeimetAbstract:Background In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer. Methods Two hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique. Results No correlation between FOLR1 mRNA expression and its specific promoter DNA methylation was found neither in type I nor in type II cancers, however, high FOLR1 mRNA expression was found to be correlated with global DNA hypomethylation in type II cancers ( p = 0.033). Strong FOLR1 mRNA expression was revealed for Grades 2-3, FIGO stages III-IV, residual disease > 0, and serous histotype. High FOLR1 expression was found to predict increased platinum sensitivity in type I cancers (odds ratio = 3.288; 1.256-10.75; p = 0.020). One-year survival analysis showed in type I cancers an independent better outcome for strong expression of FOLR1 in FIGO stage III and IV. For the entire follow up period no significant independent outcome for FOLR1 expression was revealed. In type I cancers LINE 1 DNA hypomethylation was found to exhibit a worse PFS and OS which were confirmed to be independent in multivariate COX regression model for both PFS ( p = 0.026) and OS ( p = 0.012). Conclusion No correlations were found between FOLR1 expression and its specific promoter methylation, however, high FOLR1 mRNA expression was associated with DNA hypomethylation in type II cancers. FOLR1 mRNA expression did not prove to predict clinical outcome in type II cancers, although strong FOLR1 expression generally denotes ovarian cancers with highly aggressive phenotype. In type I cancers, however, strong FOLR1 expression has been found to be a reliable indicator of improved platinum responsiveness reflecting a transient better one-year follow up outcome in highly FOLR1 expressing type I cancers. An independent prognostic role of global DNA hypomethylation was demonstrated in type I tumours.
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evaluation of Folate Receptor 1 folr1 mrna expression its specific promoter methylation and global dna hypomethylation in type i and type ii ovarian cancers
BMC Cancer, 2016Co-Authors: Sara Notaro, Daniel Reimer, Heidi Fiegl, Gabriel Schmid, Annamarie Wiedemair, Julia Rössler, Christian Marth, Alain Gustave ZeimetAbstract:Background In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer.
Robert Steinfeld - One of the best experts on this subject based on the ideXlab platform.
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molecular characterization of Folate Receptor 1 mutations delineates cerebral Folate transport deficiency
Brain, 2012Co-Authors: Marcel Grapp, I. A. Just, Tarja Linnankivi, P. Wolf, T. Lücke, Martin Häusler, Jutta Gärtner, Robert SteinfeldAbstract:Cerebral Folate transport deficiency is an inherited brain-specific Folate transport defect that is caused by mutations in the Folate Receptor 1 gene coding for Folate Receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydroFolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the Folate Receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of Folate Receptor alpha for all detected Folate Receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of Folate Receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral Folate transport deficiency.
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Molecular characterization of Folate Receptor 1 mutations delineates cerebral Folate transport deficiency.
Brain, 2012Co-Authors: Marcel Grapp, I. A. Just, Tarja Linnankivi, P. Wolf, T. Lücke, Martin Häusler, Jutta Gärtner, Robert SteinfeldAbstract:Cerebral Folate transport deficiency is an inherited brain-specific Folate transport defect that is caused by mutations in the Folate Receptor 1 gene coding for Folate Receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydroFolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the Folate Receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of Folate Receptor alpha for all detected Folate Receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of Folate Receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral Folate transport deficiency. * Abbreviations : FOLR1 : Folate Receptor 1 FRα : Folate Receptor alpha 5-MTHF : 5-methyltetrahydroFolate
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Cerebral Folate deficiency: A neurometabolic syndrome?
Molecular Genetics and Metabolism, 2011Co-Authors: Sarah Mangold, Robert Steinfeld, Thomas Opladen, Nenad Blau, Britta Weßling, Klaus Zerres, Martin HäuslerAbstract:Abstract Background Cerebral Folate deficiency (CFD) is increasingly recognized in various neurological conditions, raising the question of whether it might represent a clear-cut clinical syndrome. Methods Retrospective analysis of patients with low cerebral spinal fluid (CSF) 5-methyltetrahydroFolate (5MTHF) values was performed. Results 58 pediatric patients with low (-2nd to -3rd standard deviation) and 45 patients with very low 5MTHF values ( n = 84), motor retardation ( n = 75), epilepsy ( n = 53), ataxia ( n = 44) and pyramidal tract signs ( n = 37). There was no relationship between 5MTHF levels and the severity of clinical disease, the duration of clinical disease, distinct neurological symptoms and antiepileptic drug treatment, respectively. Genetical analysis for mutations in the Folate Receptor 1 gene proved normal in all 16 children studied. Conclusions For the majority of patients CFD is not a clear-cut neurometabolic syndrome but the common result of different genetic, metabolic or unknown processes. Nevertheless, CFD may represent a treatable disease-modifying factor which should therefore be addressed in prospective studies.
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Folate Receptor alpha defect causes cerebral Folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.
American Journal of Human Genetics, 2009Co-Authors: Robert Steinfeld, Marcel Grapp, Ralph Kraetzner, Steffi Dreha-kulaczewski, Gunther Helms, Peter Dechent, Ron A. Wevers, Salvatore Grosso, Jutta GärtnerAbstract:Sufficient Folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of Folate transport and metabolism are presently known, all of which cause systemic Folate deficiency. We identified an inherited brain-specific Folate transport defect that is caused by mutations in the Folate Receptor 1 (FOLR1) gene coding for Folate Receptor alpha (FRα). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced Folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRα or FRβ could rescue Folate binding. Furthermore, CSF Folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the Folate metabolic pathways involved in postnatal myelination and brain development.
Marcel Grapp - One of the best experts on this subject based on the ideXlab platform.
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molecular characterization of Folate Receptor 1 mutations delineates cerebral Folate transport deficiency
Brain, 2012Co-Authors: Marcel Grapp, I. A. Just, Tarja Linnankivi, P. Wolf, T. Lücke, Martin Häusler, Jutta Gärtner, Robert SteinfeldAbstract:Cerebral Folate transport deficiency is an inherited brain-specific Folate transport defect that is caused by mutations in the Folate Receptor 1 gene coding for Folate Receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydroFolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the Folate Receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of Folate Receptor alpha for all detected Folate Receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of Folate Receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral Folate transport deficiency.
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Molecular characterization of Folate Receptor 1 mutations delineates cerebral Folate transport deficiency.
Brain, 2012Co-Authors: Marcel Grapp, I. A. Just, Tarja Linnankivi, P. Wolf, T. Lücke, Martin Häusler, Jutta Gärtner, Robert SteinfeldAbstract:Cerebral Folate transport deficiency is an inherited brain-specific Folate transport defect that is caused by mutations in the Folate Receptor 1 gene coding for Folate Receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydroFolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the Folate Receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of Folate Receptor alpha for all detected Folate Receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of Folate Receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral Folate transport deficiency. * Abbreviations : FOLR1 : Folate Receptor 1 FRα : Folate Receptor alpha 5-MTHF : 5-methyltetrahydroFolate
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Folate Receptor alpha defect causes cerebral Folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.
American Journal of Human Genetics, 2009Co-Authors: Robert Steinfeld, Marcel Grapp, Ralph Kraetzner, Steffi Dreha-kulaczewski, Gunther Helms, Peter Dechent, Ron A. Wevers, Salvatore Grosso, Jutta GärtnerAbstract:Sufficient Folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of Folate transport and metabolism are presently known, all of which cause systemic Folate deficiency. We identified an inherited brain-specific Folate transport defect that is caused by mutations in the Folate Receptor 1 (FOLR1) gene coding for Folate Receptor alpha (FRα). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced Folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRα or FRβ could rescue Folate binding. Furthermore, CSF Folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the Folate metabolic pathways involved in postnatal myelination and brain development.
Daniel Reimer - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Folate Receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers
BMC Cancer, 2016Co-Authors: Sara Notaro, Daniel Reimer, Heidi Fiegl, Gabriel Schmid, Annamarie Wiedemair, Julia Rössler, Christian Marth, Alain Gustave ZeimetAbstract:Background In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer. Methods Two hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique. Results No correlation between FOLR1 mRNA expression and its specific promoter DNA methylation was found neither in type I nor in type II cancers, however, high FOLR1 mRNA expression was found to be correlated with global DNA hypomethylation in type II cancers ( p = 0.033). Strong FOLR1 mRNA expression was revealed for Grades 2-3, FIGO stages III-IV, residual disease > 0, and serous histotype. High FOLR1 expression was found to predict increased platinum sensitivity in type I cancers (odds ratio = 3.288; 1.256-10.75; p = 0.020). One-year survival analysis showed in type I cancers an independent better outcome for strong expression of FOLR1 in FIGO stage III and IV. For the entire follow up period no significant independent outcome for FOLR1 expression was revealed. In type I cancers LINE 1 DNA hypomethylation was found to exhibit a worse PFS and OS which were confirmed to be independent in multivariate COX regression model for both PFS ( p = 0.026) and OS ( p = 0.012). Conclusion No correlations were found between FOLR1 expression and its specific promoter methylation, however, high FOLR1 mRNA expression was associated with DNA hypomethylation in type II cancers. FOLR1 mRNA expression did not prove to predict clinical outcome in type II cancers, although strong FOLR1 expression generally denotes ovarian cancers with highly aggressive phenotype. In type I cancers, however, strong FOLR1 expression has been found to be a reliable indicator of improved platinum responsiveness reflecting a transient better one-year follow up outcome in highly FOLR1 expressing type I cancers. An independent prognostic role of global DNA hypomethylation was demonstrated in type I tumours.
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evaluation of Folate Receptor 1 folr1 mrna expression its specific promoter methylation and global dna hypomethylation in type i and type ii ovarian cancers
BMC Cancer, 2016Co-Authors: Sara Notaro, Daniel Reimer, Heidi Fiegl, Gabriel Schmid, Annamarie Wiedemair, Julia Rössler, Christian Marth, Alain Gustave ZeimetAbstract:Background In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer.