Functional and Structural Analysis of C-Terminal BRCA1 Missense Variants
Publication Date
April 17, 2013
Journal
PLOS ONE
Authors
Francisco Quiles, Juana Fernández Rodríguez, Roberto Mosca, Lídia Feliubadaló, et al
Volume
8
Issue
4
Pages
e61302
DOI
https://dx.plos.org/10.1371/journal.pone.0061302
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0061302
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23613828
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629201
Europe PMC
http://europepmc.org/abstract/MED/23613828
Web of Science
000317907200045
Scopus
84876245594
Mendeley
http://www.mendeley.com/research/functional-structural-analysis-cterminal-brca1-missense-variants
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Mendeley | Further Information

{"title"=>"Functional and Structural Analysis of C-Terminal BRCA1 Missense Variants", "type"=>"journal", "authors"=>[{"first_name"=>"Francisco", "last_name"=>"Quiles", "scopus_author_id"=>"57197219806"}, {"first_name"=>"Juana", "last_name"=>"Fernández-Rodríguez", "scopus_author_id"=>"36870663600"}, {"first_name"=>"Roberto", "last_name"=>"Mosca", "scopus_author_id"=>"8506336600"}, {"first_name"=>"Lídia", "last_name"=>"Feliubadaló", "scopus_author_id"=>"6602651068"}, {"first_name"=>"Eva", "last_name"=>"Tornero", "scopus_author_id"=>"36627591500"}, {"first_name"=>"Joan", "last_name"=>"Brunet", "scopus_author_id"=>"7202472537"}, {"first_name"=>"Ignacio", "last_name"=>"Blanco", "scopus_author_id"=>"26645417200"}, {"first_name"=>"Gabriel", "last_name"=>"Capellá", "scopus_author_id"=>"24368272500"}, {"first_name"=>"Miquel Àngel", "last_name"=>"Pujana", "scopus_author_id"=>"56618350700"}, {"first_name"=>"Patrick", "last_name"=>"Aloy", "scopus_author_id"=>"6701754884"}, {"first_name"=>"Alvaro", "last_name"=>"Monteiro", "scopus_author_id"=>"7102146021"}, {"first_name"=>"Conxi", "last_name"=>"Lázaro", "scopus_author_id"=>"56902756200"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84876245594", "sgr"=>"84876245594", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"23613828", "doi"=>"10.1371/journal.pone.0061302", "pui"=>"368743272"}, "id"=>"198ea81c-df89-3d2f-a5aa-e2f8d2f02cc7", "abstract"=>"Germline inactivating mutations in BRCA1 and BRCA2 genes are responsible for Hereditary Breast and Ovarian Cancer Syndrome (HBOCS). Genetic testing of these genes is available, although approximately 15% of tests identify variants of uncertain significance (VUS). Classification of these variants into pathogenic or non-pathogenic type is an important challenge in genetic diagnosis and counseling. The aim of the present study is to functionally assess a set of 7 missense VUS (Q1409L, S1473P, E1586G, R1589H, Y1703S, W1718L and G1770V) located in the C-terminal region of BRCA1 by combining in silico prediction tools and structural analysis with a transcription activation (TA) assay. The in silico prediction programs gave discrepant results making its interpretation difficult. Structural analysis of the three variants located in the BRCT domains (Y1703S, W1718L and G1770V) reveals significant alterations of BRCT structure. The TA assay shows that variants Y1703S, W1718L and G1770V dramatically compromise the transcriptional activity of BRCA1, while variants Q1409L, S1473P, E1586G and R1589H behave like wild-type BRCA1. In conclusion, our results suggest that variants Y1703S, W1718L and G1770V can be classified as likely pathogenic BRCA1 mutations.", "link"=>"http://www.mendeley.com/research/functional-structural-analysis-cterminal-brca1-missense-variants", "reader_count"=>53, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>5, "Researcher"=>13, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>3, "Student > Master"=>3, "Other"=>5, "Student > Bachelor"=>5, "Lecturer"=>2, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>5, "Researcher"=>13, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>3, "Student > Master"=>3, "Other"=>5, "Student > Bachelor"=>5, "Lecturer"=>2, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Biochemistry, Genetics and Molecular Biology"=>10, "Agricultural and Biological Sciences"=>23, "Medicine and Dentistry"=>11, "Physics and Astronomy"=>1, "Psychology"=>1, "Social Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}, "Unspecified"=>{"Unspecified"=>6}}, "reader_count_by_country"=>{"United States"=>1, "China"=>1, "Nigeria"=>1, "Spain"=>1}, "group_count"=>5}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1026819"], "description"=>"<p>This Figure shows the position of missense variants analyzed in the present study (black arrows) and the negative controls (closed gray arrows, underlined) within the vector used in the TA experiments.</p>", "links"=>[], "tags"=>["Computational biology", "Macromolecular structure analysis", "protein structure", "genetics", "Genetic mutation", "mutagenesis", "Cancer genetics", "Gene function", "Obstetrics and gynecology", "breast cancer", "oncology", "Cancer detection and diagnosis", "Cancer screening", "Cancer risk factors", "Genetic causes of cancer", "Cancers and neoplasms", "Gynecological tumors", "Ovarian cancer", "Breast tumors", "Basic cancer research", "depicting", "c-terminal", "brca", "missense", "variants"], "article_id"=>684325, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francisco Quiles", "Juana Fernández-Rodríguez", "Roberto Mosca", "Lídia Feliubadaló", "Eva Tornero", "Joan Brunet", "Ignacio Blanco", "Gabriel Capellá", "Miquel Angel Pujana", "Patrick Aloy", "Alvaro Monteiro", "Conxi Lázaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061302.g001", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Illustration_depicting_the_location_of_the_C_terminal_BRCA_missense_variants_and_negative_controls_/684325", "title"=>"Illustration depicting the location of the C-terminal BRCA missense variants and negative controls.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-17 01:12:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1026820"], "description"=>"<p>Percentage of transcriptional activity was expressed as percentage relative to the wild-type construct. Experiments were performed in triplicate and normalized against the <i>Renilla</i> luciferase internal control. Results are shown in bars: gray for controls and black for variants.</p>", "links"=>[], "tags"=>["Computational biology", "Macromolecular structure analysis", "protein structure", "genetics", "Genetic mutation", "mutagenesis", "Cancer genetics", "Gene function", "Obstetrics and gynecology", "breast cancer", "oncology", "Cancer detection and diagnosis", "Cancer screening", "Cancer risk factors", "Genetic causes of cancer", "Cancers and neoplasms", "Gynecological tumors", "Ovarian cancer", "Breast tumors", "Basic cancer research", "assay", "studied", "missense"], "article_id"=>684326, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francisco Quiles", "Juana Fernández-Rodríguez", "Roberto Mosca", "Lídia Feliubadaló", "Eva Tornero", "Joan Brunet", "Ignacio Blanco", "Gabriel Capellá", "Miquel Angel Pujana", "Patrick Aloy", "Alvaro Monteiro", "Conxi Lázaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061302.g002", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Results_of_functional_assay_of_the_studied_missense_variants_/684326", "title"=>"Results of functional assay of the studied missense variants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-17 01:12:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1026826"], "description"=>"<p>Each predictor yields its own type of results, usually quantitative and categorical. We have chosen the most representative of each.</p>1<p>Predictors PON-P and Condel integrate results from other predictors run in their own servers; as PolyPhen-2 versions and their results differ if they are run in the PolyPhen-2 website or the other 2, all of them are shown for comparison. <sup>2</sup>Classification of variants in different classes according to Align-GVGD algorithm (Align-Grantham Variation Grantham Deviation; <a href=\"http://agvgd.iarc.fr\" target=\"_blank\">http://agvgd.iarc.fr</a>), C65 means “Most likely to interfere with function, C0 means “least likely” (possible classes are: C65> C55>C45>C35>C25>C15>C0).</p><p>Abbreviations: Prob.-Probability; Pred.-Prediction; Funct.-Functional; Accur.-Accuracy; ΔΔG–ΔΔG value (kcal/mol); Del-Deleterious; N-Neutral; Dest- Destabilizing; P-Pathogenic; UV-Unknown Variant.</p>", "links"=>[], "tags"=>["Computational biology", "Macromolecular structure analysis", "protein structure", "genetics", "Genetic mutation", "mutagenesis", "Cancer genetics", "Gene function", "Obstetrics and gynecology", "breast cancer", "oncology", "Cancer detection and diagnosis", "Cancer screening", "Cancer risk factors", "Genetic causes of cancer", "Cancers and neoplasms", "Gynecological tumors", "Ovarian cancer", "Breast tumors", "Basic cancer research", "predictions", "pathogenicity", "variants", "presented"], "article_id"=>684332, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francisco Quiles", "Juana Fernández-Rodríguez", "Roberto Mosca", "Lídia Feliubadaló", "Eva Tornero", "Joan Brunet", "Ignacio Blanco", "Gabriel Capellá", "Miquel Angel Pujana", "Patrick Aloy", "Alvaro Monteiro", "Conxi Lázaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061302.t001", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_silico_predictions_for_pathogenicity_of_the_variants_presented_in_this_study_/684332", "title"=>"<i>In silico</i> predictions for pathogenicity of the variants presented in this study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-17 01:12:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1026824"], "description"=>"<p>Representation of the structure of the BRCT tandem repeat from human BRCA1 in complex with a binding phosphopeptide (with the typical binding motif pSer-X-X-Phe, PDB ID 1t2v): in blue, the N-terminal repeat (BRCT-N); in red, the C-terminal repeat (BRCT-C); in green, the linker region between the two; in cyan, the phosphopeptide with the phosphoserine and the key binding residue Phe(+3); in, magenta the three mutated residues. Y1703 (A) forms a hydrogen bond with H1746 and is adjacent to K1702, which binds directly to the pSer residue in the phosphopeptide. W1718 (B) fills the internal core and stabilizes the BRCT-N domain. G1770 (C) gives the loop connecting the β1 strand with α1-helix in the BRCT-C repeat the necessary flexibility to form a tight turn, bringing the residues N1774 and M1775 close to the phosphopeptide for interaction with the Phe(+3) key residue.</p>", "links"=>[], "tags"=>["Computational biology", "Macromolecular structure analysis", "protein structure", "genetics", "Genetic mutation", "mutagenesis", "Cancer genetics", "Gene function", "Obstetrics and gynecology", "breast cancer", "oncology", "Cancer detection and diagnosis", "Cancer screening", "Cancer risk factors", "Genetic causes of cancer", "Cancers and neoplasms", "Gynecological tumors", "Ovarian cancer", "Breast tumors", "Basic cancer research", "missense", "variants", "lying", "BRCA1", "brct"], "article_id"=>684330, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francisco Quiles", "Juana Fernández-Rodríguez", "Roberto Mosca", "Lídia Feliubadaló", "Eva Tornero", "Joan Brunet", "Ignacio Blanco", "Gabriel Capellá", "Miquel Angel Pujana", "Patrick Aloy", "Alvaro Monteiro", "Conxi Lázaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061302.g003", "stats"=>{"downloads"=>3, "page_views"=>144, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_analysis_of_missense_variants_lying_in_the_BRCA1_BRCT_domain_/684330", "title"=>"Structural analysis of missense variants lying in the BRCA1 BRCT domain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-17 01:12:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/1026827"], "description"=>"<div><p>Germline inactivating mutations in <i>BRCA1</i> and <i>BRCA2</i> genes are responsible for Hereditary Breast and Ovarian Cancer Syndrome (HBOCS). Genetic testing of these genes is available, although approximately 15% of tests identify variants of uncertain significance (VUS). Classification of these variants into pathogenic or non-pathogenic type is an important challenge in genetic diagnosis and counseling. The aim of the present study is to functionally assess a set of 7 missense VUS (Q1409L, S1473P, E1586G, R1589H, Y1703S, W1718L and G1770V) located in the C-terminal region of BRCA1 by combining <i>in silico</i> prediction tools and structural analysis with a transcription activation (TA) assay. The <i>in silico</i> prediction programs gave discrepant results making its interpretation difficult. Structural analysis of the three variants located in the BRCT domains (Y1703S, W1718L and G1770V) reveals significant alterations of BRCT structure. The TA assay shows that variants Y1703S, W1718L and G1770V dramatically compromise the transcriptional activity of BRCA1, while variants Q1409L, S1473P, E1586G and R1589H behave like wild-type BRCA1. In conclusion, our results suggest that variants Y1703S, W1718L and G1770V can be classified as likely pathogenic <i>BRCA1</i> mutations.</p> </div>", "links"=>[], "tags"=>["Computational biology", "Macromolecular structure analysis", "protein structure", "genetics", "Genetic mutation", "mutagenesis", "Cancer genetics", "Gene function", "Obstetrics and gynecology", "breast cancer", "oncology", "Cancer detection and diagnosis", "Cancer screening", "Cancer risk factors", "Genetic causes of cancer", "Cancers and neoplasms", "Gynecological tumors", "Ovarian cancer", "Breast tumors", "Basic cancer research", "c-terminal", "BRCA1", "missense"], "article_id"=>684333, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Francisco Quiles", "Juana Fernández-Rodríguez", "Roberto Mosca", "Lídia Feliubadaló", "Eva Tornero", "Joan Brunet", "Ignacio Blanco", "Gabriel Capellá", "Miquel Angel Pujana", "Patrick Aloy", "Alvaro Monteiro", "Conxi Lázaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0061302", "stats"=>{"downloads"=>10, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_and_Structural_Analysis_of_C_Terminal_BRCA1_Missense_Variants_/684333", "title"=>"Functional and Structural Analysis of C-Terminal BRCA1 Missense Variants", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-17 01:12:13"}

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Relative Metric

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