Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology
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{"title"=>"Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: Cellular model of pathology", "type"=>"journal", "authors"=>[{"first_name"=>"Astrid C.", "last_name"=>"Haugen", "scopus_author_id"=>"7006262871"}, {"first_name"=>"Nicholas A.", "last_name"=>"Di Prospero", "scopus_author_id"=>"26326239600"}, {"first_name"=>"Joel S.", "last_name"=>"Parker", "scopus_author_id"=>"7404595426"}, {"first_name"=>"Rick D.", "last_name"=>"Fannin", "scopus_author_id"=>"7003833030"}, {"first_name"=>"Jeff", "last_name"=>"Chou", "scopus_author_id"=>"7402094320"}, {"first_name"=>"Joel N.", "last_name"=>"Meyer", "scopus_author_id"=>"9234221700"}, {"first_name"=>"Christopher", "last_name"=>"Halweg", "scopus_author_id"=>"15727596500"}, {"first_name"=>"Jennifer B.", "last_name"=>"Collins", "scopus_author_id"=>"7404949513"}, {"first_name"=>"Alexandra", "last_name"=>"Durr", "scopus_author_id"=>"24741153500"}, {"first_name"=>"Kenneth", "last_name"=>"Fischbeck", "scopus_author_id"=>"7004500500"}, {"first_name"=>"Bennett", "last_name"=>"Van Houten", "scopus_author_id"=>"7005898292"}], "year"=>2010, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"358308129", "sgr"=>"76749143747", "issn"=>"15537390", "pmid"=>"20090835", "scopus"=>"2-s2.0-76749143747", "doi"=>"10.1371/journal.pgen.1000812", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)"}, "id"=>"e2227241-bf87-341e-9225-689a93c08404", "abstract"=>"The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.", "link"=>"http://www.mendeley.com/research/altered-gene-expression-dna-damage-peripheral-blood-cells-friedreichs-ataxia-patients-cellular-model-7", "reader_count"=>17, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>3, "Agricultural and Biological Sciences"=>8, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Germany"=>1}, "group_count"=>1}

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  • {"files"=>["https://ndownloader.figshare.com/files/430959", "https://ndownloader.figshare.com/files/430969", "https://ndownloader.figshare.com/files/430979", "https://ndownloader.figshare.com/files/430995", "https://ndownloader.figshare.com/files/431011", "https://ndownloader.figshare.com/files/431018", "https://ndownloader.figshare.com/files/431025", "https://ndownloader.figshare.com/files/431035", "https://ndownloader.figshare.com/files/431043", "https://ndownloader.figshare.com/files/431053", "https://ndownloader.figshare.com/files/431064", "https://ndownloader.figshare.com/files/431074", "https://ndownloader.figshare.com/files/431082", "https://ndownloader.figshare.com/files/431112", "https://ndownloader.figshare.com/files/431138", "https://ndownloader.figshare.com/files/431148", "https://ndownloader.figshare.com/files/431183", "https://ndownloader.figshare.com/files/431203", "https://ndownloader.figshare.com/files/431220"], "description"=>"<div><p>The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (<em>p</em><0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.</p></div>", "links"=>[], "tags"=>["altered", "dna", "peripheral", "cells", "ataxia", "cellular", "pathology"], "article_id"=>145056, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000812.s001", "https://dx.doi.org/10.1371/journal.pgen.1000812.s002", "https://dx.doi.org/10.1371/journal.pgen.1000812.s003", "https://dx.doi.org/10.1371/journal.pgen.1000812.s004", "https://dx.doi.org/10.1371/journal.pgen.1000812.s005", "https://dx.doi.org/10.1371/journal.pgen.1000812.s006", "https://dx.doi.org/10.1371/journal.pgen.1000812.s007", "https://dx.doi.org/10.1371/journal.pgen.1000812.s008", "https://dx.doi.org/10.1371/journal.pgen.1000812.s009", "https://dx.doi.org/10.1371/journal.pgen.1000812.s010", "https://dx.doi.org/10.1371/journal.pgen.1000812.s011", "https://dx.doi.org/10.1371/journal.pgen.1000812.s012", "https://dx.doi.org/10.1371/journal.pgen.1000812.s013", "https://dx.doi.org/10.1371/journal.pgen.1000812.s014", "https://dx.doi.org/10.1371/journal.pgen.1000812.s015", "https://dx.doi.org/10.1371/journal.pgen.1000812.s016", "https://dx.doi.org/10.1371/journal.pgen.1000812.s017", "https://dx.doi.org/10.1371/journal.pgen.1000812.s018", "https://dx.doi.org/10.1371/journal.pgen.1000812.s019"], "stats"=>{"downloads"=>5, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Altered_Gene_Expression_and_DNA_Damage_in_Peripheral_Blood_Cells_from_Friedreich_s_Ataxia_Patients_Cellular_Model_of_Pathology/145056", "title"=>"Altered Gene Expression and DNA Damage in Peripheral Blood Cells from Friedreich's Ataxia Patients: Cellular Model of Pathology", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-01-15 01:24:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/868392"], "description"=>"<p>n = significant genes; selected categories and their genes are displayed.</p><p>Frataxin levels, Age of Diagnosis, ICARS<sup>1</sup>; n = genes found by EPIG analysis.</p><p>ICARS<sup>2</sup>; n = genes found by supervised correlation analysis, where the <i>r</i> and <i>P</i> values between gene expression and ICARS score were calculated.</p><p>BP = Gene ontology system, biological process.</p><p>CC = Gene ontology system, cellular component.</p><p>MF = Gene ontology system, molecular function.</p>", "links"=>[], "tags"=>["biomarkers", "associations", "differential"], "article_id"=>538835, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000812.t002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Potential_biomarkers_of_FRDA_gene_associations_to_clinical_data_based_on_differential_expression_/538835", "title"=>"Potential biomarkers of FRDA: gene associations to clinical data based on differential expression.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-01-15 02:27:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/867687"], "description"=>"<p>Significantly regulated genes (SAM FDR<0.023%; n = 1,370) from FRDA children versus healthy young adults were grouped according to the gene ontology category of biological process (<i>p</i>≤0.05 in <i>updown</i>, <i>over</i>, or <i>under</i> [expression] output lists). The percent of total (displayed with a gray ball) is based on the number of significantly changed genes out of the total number of genes assigned to each gene ontology term. The change in expression for each GO term is depicted in yellow for upregulation and blue for downregulation.</p>", "links"=>[], "tags"=>["classifications"], "article_id"=>538138, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000812.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Selected_gene_classifications_according_to_biological_processes_/538138", "title"=>"Selected gene classifications according to biological processes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:15:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/867834"], "description"=>"<p>(A) A common gene signature is representative of a genotoxic stress response found by Gene Set Analysis. Twenty-three genotoxic stress response gene sets were searched for common genes. This heat map, generated by unsupervised clustering, displays the genes present in at least 6 of the 23 gene sets and compares transcript levels between FRDA patients, the adult and children cohorts, and controls. Yellow = upregulated; Blue = downregulated. C = Control; P = Patient. Note that while three patients and one control did not segregate with their respective groups, all adult patients and controls clustered in two separate groups in this unsupervised clustering. (B) Heat-map generated by unsupervised clustering of FRDA and control samples, which displays the overlap of significantly differentially expressed genes (SAM FDR<0.023%; n = 228) in the FRDA children and FRDA adults (overlap <i>p</i>≤0.007). C = control; P = patient. (C) A selected list of significant GO groups representing the overlap gene list described in (B). All controls used for comparison to the FRDA children are young adults (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000812#pgen.1000812.s005\" target=\"_blank\">Table S1</a>). The percent of total (displayed with a gray ball) is based on the number of significantly changed genes out of the total number of genes assigned to each gene ontology term. The gene number for each GO group is shown with a blue bar, the intensity of which is indicative of the <i>p</i>-value.</p>", "links"=>[], "tags"=>["responses", "children", "adults"], "article_id"=>538278, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000812.g002", "stats"=>{"downloads"=>3, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analogous_gene_expression_responses_in_blood_from_children_and_adults_with_FRDA_/538278", "title"=>"Analogous gene expression responses in blood from children and adults with FRDA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:17:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/868290"], "description"=>"<p>Data presented in this study are consistent with a dysregulation of mitochondrial function, decreased oxidative phosphorylation, increased ROS production, and subsequent mitochondrial and nuclear DNA damage. These factors contribute to decreased signaling and altered DNA transactions, which are likely to result in subsequent loss of protein synthesis and decreased protein degradation, as suggested in the transcription profiling. These alterations may cause tissue damage, altered immune response, and the clinical pathology associated with FRDA.</p>", "links"=>[], "tags"=>["ataxia", "pathology"], "article_id"=>538735, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000812.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_of_Friedreich_s_ataxia_pathology_based_on_this_study_/538735", "title"=>"Model of Friedreich's ataxia pathology based on this study.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:25:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/868117"], "description"=>"<p>(A) Real-time PCR of frataxin levels in all patients with available RNA (27) were compared to controls (10). Levels of frataxin are relative to the average Δ<i>C</i><sub>T</sub> of the controls (dotted line). The error bars represent standard deviations. Brackets encompass the patients stratified by their expression distribution into those expressing higher levels of frataxin (n = 6) and those expressing lower levels of frataxin (n = 21) (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000812#pgen.1000812.s001\" target=\"_blank\">Figure S1</a>). (B) Global gene expression changes were analyzed in the patients with low levels of frataxin vs. patients with high levels of frataxin. Significantly differentially expressed genes (SAM FDR≤8%; <i>p</i>≤0.05; n = 973) were further examined for gene ontology groups categorized by biological process. The same list of genes was analyzed with IPA (Ingenuity Systems), which identified significant biological functions and canonical pathways. All gene groups contain mostly downregulated genes, indicating compromised mitochondrial and biosynthetic function in patients with the lowest expression of frataxin. (C) Age of onset plotted against the Real-time PCR frataxin levels yields a correlation of <i>r<sup>2</sup></i> = 0.305 (<i>p</i> = 0.00277).</p>", "links"=>[], "tags"=>["levels", "frataxin", "correlate", "onset", "compromised", "mitochondrial", "biosynthetic"], "article_id"=>538552, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000812.g004", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Patients_with_lower_levels_of_frataxin_correlate_with_age_of_onset_of_disease_and_have_more_compromised_mitochondrial_and_protein_biosynthetic_function_/538552", "title"=>"Patients with lower levels of frataxin correlate with age of onset of disease and have more compromised mitochondrial and protein biosynthetic function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:22:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/867975"], "description"=>"<p>These data represent the number of excess lesions found per 10 kb of DNA from both mtDNA and nDNA genomes in FRDA patients as compared to the controls. A significant number of nuclear (0.53 lesions/10 kb) and mitochondrial DNA lesions (0.81 lesions/10 kb) were observed (<i>p</i><0.0001, respectively, by Mann-Whitney U test). There is a significantly higher number of mitochondrial lesions than nuclear lesions (<i>p</i><0.002 by Mann-Whitney U test), and both types of lesions are highly correlated (<i>p</i><0.0001 by Spearman's Rank Correlation). Error bars represent the standard error of the mean.</p>", "links"=>[], "tags"=>["mitochondrial", "dna", "qpcr", "47", "patients", "frda", "15"], "article_id"=>538415, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000812.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nuclear_and_mitochondrial_DNA_damage_are_identified_by_QPCR_analysis_of_blood_DNA_from_47_patients_with_FRDA_and_15_controls_/538415", "title"=>"Nuclear and mitochondrial DNA damage are identified by QPCR analysis of blood DNA from 47 patients with FRDA and 15 controls.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-15 02:20:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/868430"], "description"=>"<p>GSA was performed using the Molecular Signatures Database. Significantly enriched gene sets included 23 sets associated to genotoxic stress response.</p>", "links"=>[], "tags"=>["demonstrates", "dna", "frda"], "article_id"=>538881, "categories"=>["Biochemistry", "Genetics", "Cancer", "Neuroscience", "Molecular Biology"], "users"=>["Astrid C. Haugen", "Nicholas A. Di Prospero", "Joel S. Parker", "Rick D. Fannin", "Jeff Chou", "Joel N. Meyer", "Christopher Halweg", "Jennifer B. Collins", "Alexandra Durr", "Kenneth Fischbeck", "Bennett Van Houten"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000812.t001", "stats"=>{"downloads"=>5, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_Set_Analysis_demonstrates_a_signature_of_DNA_damage_in_FRDA_patients_/538881", "title"=>"Gene Set Analysis demonstrates a signature of DNA damage in FRDA patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-01-15 02:28:01"}

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Relative Metric

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