A Combined Nucleic Acid and Protein Analysis in Friedreich Ataxia: Implications for Diagnosis, Pathogenesis and Clinical Trial Design
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{"title"=>"A combined nucleic acid and protein analysis in Friedreich ataxia: Implications for diagnosis, pathogenesis and clinical trial design", "type"=>"journal", "authors"=>[{"first_name"=>"Francesco", "last_name"=>"Saccà", "scopus_author_id"=>"8216312200"}, {"first_name"=>"Giorgia", "last_name"=>"Puorro", "scopus_author_id"=>"37023312700"}, {"first_name"=>"Antonella", "last_name"=>"Antenora", "scopus_author_id"=>"36142780000"}, {"first_name"=>"Angela", "last_name"=>"Marsili", "scopus_author_id"=>"37075078400"}, {"first_name"=>"Alessandra", "last_name"=>"Denaro", "scopus_author_id"=>"54894523700"}, {"first_name"=>"Raffaele", "last_name"=>"Piro", "scopus_author_id"=>"25950576000"}, {"first_name"=>"Pierpaolo", "last_name"=>"Sorrentino", "scopus_author_id"=>"37075966300"}, {"first_name"=>"Chiara", "last_name"=>"Pane", "scopus_author_id"=>"37075374800"}, {"first_name"=>"Alessandra", "last_name"=>"Tessa", "scopus_author_id"=>"7004428063"}, {"first_name"=>"Vincenzo Brescia", "last_name"=>"Morra", "scopus_author_id"=>"6603751678"}, {"first_name"=>"Sergio", "last_name"=>"Cocozza", "scopus_author_id"=>"7003365765"}, {"first_name"=>"Giuseppe", "last_name"=>"de Michele", "scopus_author_id"=>"7005917994"}, {"first_name"=>"Filippo M.", "last_name"=>"Santorelli", "scopus_author_id"=>"7006490405"}, {"first_name"=>"Alessandro", "last_name"=>"Filla", "scopus_author_id"=>"55411798200"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"361433583", "sgr"=>"79952592026", "issn"=>"19326203", "pmid"=>"21412413", "scopus"=>"2-s2.0-79952592026", "doi"=>"10.1371/journal.pone.0017627", "isbn"=>"1932-6203 (Electronic) 1932-6203 (Linking)"}, "id"=>"81ab79aa-9d82-341c-a4ea-a95993f247b0", "abstract"=>"BACKGROUND: Friedreich's ataxia (FRDA) is the most common hereditary ataxia among caucasians. The molecular defect in FRDA is the trinucleotide GAA expansion in the first intron of the FXN gene, which encodes frataxin. No studies have yet reported frataxin protein and mRNA levels in a large cohort of FRDA patients, carriers and controls.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: We enrolled 24 patients with classic FRDA phenotype (cFA), 6 late onset FRDA (LOFA), all homozygous for GAA expansion, 5 pFA cases who harbored the GAA expansion in compound heterozygosis with FXN point mutations (namely, p.I154F, c.482+3delA, p.R165P), 33 healthy expansion carriers, and 29 healthy controls. DNA was genotyped for GAA expansion, mRNA/FXN was quantified in real-time, and frataxin protein was measured using lateral-flow immunoassay in peripheral blood mononuclear cells (PBMCs). Mean residual levels of frataxin, compared to controls, were 35.8%, 65.6%, 33%, and 68.7% in cFA, LOFA, pFA and healthy carriers, respectively. Comparison of both cFA and pFA with controls resulted in 100% sensitivity and specificity, but there was overlap between LOFA, carriers and controls. Frataxin levels correlated inversely with GAA1 and GAA2 expansions, and directly with age at onset. Messenger RNA expression was reduced to 19.4% in cFA, 50.4% in LOFA, 52.7% in pFA, 53.0% in carriers, as compared to controls (p<0.0001). mRNA levels proved to be diagnostic when comparing cFA with controls resulting in 100% sensitivity and specificity. In cFA and LOFA patients mRNA levels correlated directly with protein levels and age at onset, and inversely with GAA1 and GAA2.\\n\\nCONCLUSION/SIGNIFICANCE: We report the first explorative study on combined frataxin and mRNA levels in PBMCs from a cohort of FRDA patients, carriers and healthy individuals. Lateral-flow immunoassay differentiated cFA and pFA patients from controls, whereas determination of mRNA in q-PCR was sensitive and specific only in cFA.", "link"=>"http://www.mendeley.com/research/combined-nucleic-acid-protein-analysis-friedreich-ataxia-implications-diagnosis-pathogenesis-clinica-3", "reader_count"=>28, "reader_count_by_academic_status"=>{"Researcher"=>7, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>7, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Professor"=>2, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Researcher"=>7, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>7, "Other"=>2, "Student > Master"=>2, "Student > Bachelor"=>4, "Professor"=>2, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>12, "Medicine and Dentistry"=>5, "Chemistry"=>2, "Immunology and Microbiology"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Chemistry"=>{"Chemistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>12}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Turkey"=>1, "Italy"=>1, "United Kingdom"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/791888"], "description"=>"<p>A) correlation between <i>FXN</i> mRNA and protein levels cFA and LOFA patients (p<0.001, R<sup>2</sup> = 0.4058); B) correlation between <i>FXN</i> mRNA levels and age at onset in cFA and LOFA patients (p<0.0001, R<sup>2</sup> = 0.3905); C) correlation between <i>FXN</i> levels and GAA1 for cFA and LOFA (p<0.01, R<sup>2</sup> = 0.2364); D) correlation between <i>FXN</i> levels and GAA2 for cFA and LOFA (p<0.05, R<sup>2</sup> = 0.1750); E) correlation between <i>FXN</i> mRNA levels and GAA2 for carriers (p<0.0001, R<sup>2</sup> = 0.4667); F) correlation between <i>FXN</i> mRNA and protein levels in carriers (p<0.02, R<sup>2</sup> = 0.2167).</p>", "links"=>[], "tags"=>["mrna"], "article_id"=>462243, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FXN_mRNA_correlation_analysis_/462243", "title"=>"<i>FXN</i> mRNA correlation analysis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-11 00:37:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/396128"], "description"=>"<div><h3>Background</h3><p>Friedreich's ataxia (FRDA) is the most common hereditary ataxia among caucasians. The molecular defect in FRDA is the trinucleotide GAA expansion in the first intron of the <em>FXN</em> gene, which encodes frataxin. No studies have yet reported frataxin protein and mRNA levels in a large cohort of FRDA patients, carriers and controls.</p> <h3>Methodology/Principal Findings</h3><p>We enrolled 24 patients with classic FRDA phenotype (cFA), 6 late onset FRDA (LOFA), all homozygous for GAA expansion, 5 pFA cases who harbored the GAA expansion in compound heterozygosis with <em>FXN</em> point mutations (namely, p.I154F, c.482+3delA, p.R165P), 33 healthy expansion carriers, and 29 healthy controls. DNA was genotyped for GAA expansion, mRNA/<em>FXN</em> was quantified in real-time, and frataxin protein was measured using lateral-flow immunoassay in peripheral blood mononuclear cells (PBMCs). Mean residual levels of frataxin, compared to controls, were 35.8%, 65.6%, 33%, and 68.7% in cFA, LOFA, pFA and healthy carriers, respectively. Comparison of both cFA and pFA with controls resulted in 100% sensitivity and specificity, but there was overlap between LOFA, carriers and controls. Frataxin levels correlated inversely with GAA1 and GAA2 expansions, and directly with age at onset. Messenger RNA expression was reduced to 19.4% in cFA, 50.4% in LOFA, 52.7% in pFA, 53.0% in carriers, as compared to controls (p<0.0001). mRNA levels proved to be diagnostic when comparing cFA with controls resulting in 100% sensitivity and specificity. In cFA and LOFA patients mRNA levels correlated directly with protein levels and age at onset, and inversely with GAA1 and GAA2.</p> <h3>Conclusion/Significance</h3><p>We report the first explorative study on combined frataxin and mRNA levels in PBMCs from a cohort of FRDA patients, carriers and healthy individuals. Lateral-flow immunoassay differentiated cFA and pFA patients from controls, whereas determination of mRNA in q-PCR was sensitive and specific only in cFA.</p> </div>", "links"=>[], "tags"=>["nucleic", "friedreich", "implications", "pathogenesis"], "article_id"=>138244, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Combined_Nucleic_Acid_and_Protein_Analysis_in_Friedreich_Ataxia_Implications_for_Diagnosis_Pathogenesis_and_Clinical_Trial_Design/138244", "title"=>"A Combined Nucleic Acid and Protein Analysis in Friedreich Ataxia: Implications for Diagnosis, Pathogenesis and Clinical Trial Design", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-11 02:17:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/792085"], "description"=>"<p>A) Bimodal distribution of GAA2 repeats in carriers; B) skewed distribution of <i>FXN</i> mRNA levels in carriers; C) skewed distribution of frataxin protein levels in carriers.</p>", "links"=>[], "tags"=>["mrna", "frataxin"], "article_id"=>462439, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Non_normal_distribution_of_GAA2_FXN_mRNA_and_frataxin_protein_in_carriers_/462439", "title"=>"Non normal distribution of GAA2, <i>FXN</i> mRNA and frataxin protein in carriers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-11 00:40:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/791516"], "description"=>"<p>A) correlation between frataxin levels and GAA1 repeats in cFA and LOFA pateints (p<0.0001, R<sup>2</sup> = 0.4632); B) correlation between frataxin levels and GAA2 repeats in cFA and LOFA patients (p<0.001, R<sup>2</sup> = 0.3886); C) correlation between frataxin levels and age at onset for cFA and LOFA (p<0.001, R<sup>2</sup> = 0.3577); D) correlation between frataxin and GAA2 in carriers (p<0.05, R<sup>2</sup> = 0.1745); E) correlation between frataxin levels and GAA1 in controls (p<0.05, R<sup>2</sup> = 0.1634); F) correlation between frataxin levels and GAA2 in controls (p<0.05, R<sup>2</sup> = 0.1463).</p>", "links"=>[], "tags"=>["genetics and genomics", "immunology", "pathology", "neurological disorders", "Biochemistry"], "article_id"=>461864, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Protein_correlation_analysis_/461864", "title"=>"Protein correlation analysis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-11 00:31:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/791742"], "description"=>"<p>Box and wiskers plots (min to max) of <i>FXN</i> mRNA relative expression levels in cFA (n = 23), LOFA (n = 6), carriers (n = 29), controls (n = 25), and pFA (n = 5). Statistical significance for all groups compared to controls is p<0.0001.</p>", "links"=>[], "tags"=>["mrna", "levels"], "article_id"=>462094, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_FXN_mRNA_levels_in_PBMC_/462094", "title"=>"<i>FXN</i> mRNA levels in PBMC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-11 00:34:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/792190"], "description"=>"<p>Classic FRDA (cFA), point mutation FA (pFA), late onset FA (LOFA), carriers, and controls. All data are presented as mean±SD.</p>", "links"=>[], "tags"=>["genotyping"], "article_id"=>462550, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627.t001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Demographics_and_genotyping_for_all_subjects_/462550", "title"=>"Demographics and genotyping for all subjects.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-11 00:42:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/791370"], "description"=>"<p>Box and wiskers plot (min to max) of frataxin levels in cFA (n = 24), LOFA (n = 5), carriers (n = 33), controls (n = 29), and pFA (n = 5). Statistical significance is indicated after comparison to cFA (**p>0.01, ***p<0.001).</p>", "links"=>[], "tags"=>["levels"], "article_id"=>461722, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627.g001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frataxin_protein_levels_in_PMBCs_/461722", "title"=>"Frataxin protein levels in PMBCs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-03-11 00:28:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/792231"], "description"=>"<p>Demographics, neurological data, frataxin protein and <i>FXN</i> mRNA levels in pFA. Frataxin protein % and <i>FXN</i> mRNA levels % are expressed as relative to the control group.</p>", "links"=>[], "tags"=>["mutation", "fa"], "article_id"=>462590, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Neuroscience", "Immunology"], "users"=>["Francesco Saccà", "Giorgia Puorro", "Antonella Antenora", "Angela Marsili", "Alessandra Denaro", "Raffaele Piro", "Pierpaolo Sorrentino", "Chiara Pane", "Alessandra Tessa", "Vincenzo Brescia Morra", "Sergio Cocozza", "Giuseppe De Michele", "Filippo M. Santorelli", "Alessandro Filla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0017627.t002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Point_mutation_FA_patients_/462590", "title"=>"Point mutation FA patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-03-11 00:43:10"}

PMC Usage Stats | Further Information

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