Identification and Glycerol-Induced Correction of Misfolding Mutations in the X-Linked Mental Retardation Gene CASK
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{"title"=>"Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK", "type"=>"journal", "authors"=>[{"first_name"=>"Leslie E.W.", "last_name"=>"LaConte", "scopus_author_id"=>"57188550768"}, {"first_name"=>"Vrushali", "last_name"=>"Chavan", "scopus_author_id"=>"56058459400"}, {"first_name"=>"Konark", "last_name"=>"Mukherjee", "scopus_author_id"=>"7202136681"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"24505460", "pui"=>"372535062", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0088276", "scopus"=>"2-s2.0-84895513644", "sgr"=>"84895513644"}, "id"=>"589967af-270d-3cce-bc55-a9793b45e7a9", "abstract"=>"The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future.", "link"=>"http://www.mendeley.com/research/identification-glycerolinduced-correction-misfolding-mutations-xlinked-mental-retardation-gene-cask", "reader_count"=>14, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>2, "Student > Master"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>2, "Student > Master"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>5, "Medicine and Dentistry"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"China"=>1, "Spain"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1377348"], "description"=>"<p>Images were obtained with a 63X Plan-apochromat 1.4 N.A oil lens. White arrows indicate representative intracellular aggregates. Insert shows higher magnification.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "localization", "gfp-hcask", "mutants", "hek-393"], "article_id"=>927072, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.g003", "stats"=>{"downloads"=>1, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Subcellular_localization_of_GFP_hCASK_and_GFP_hCASK_mutants_in_HEK_393_cells_/927072", "title"=>"Subcellular localization of GFP-hCASK and GFP-hCASK mutants in HEK-393 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377351"], "description"=>"<p>Images of HEK cells transfected with <i>A)</i> GFP-CASK-Y728C or <i>B)</i> GFP-CASK-W919R were obtained with a 63X Plan-apochromat 1.4 N.A oil lens. First column shows aggregated GFP-CASK protein. Panels labeled “mCherry” show cells that were co-transfected with GFP-CASK and mCherry, which remains cytosolic. Panels labeled “Thioflavin T” represent coverslips that were fixed and then stained with Thioflavin T, which shows enhanced fluorescence in the presence of amyloid fibrils. Panels labeled “Golgi-RFP” represent coverslips that were treated with CellLight® Golgi-RFP which labels the Golgi network. Third column shows an overlay, demonstrating that aggregates are cytosolic (mCherry, Golgi-RFP) but not amyloid in nature (Thioflavin T).</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics"], "article_id"=>927075, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.g004", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characterization_of_aggregates_/927075", "title"=>"Characterization of aggregates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377352"], "description"=>"<p>Lysates from HEK-293 cells co-transfected with GFP-CASK (wild-type or mutants R28L, Y268H, or P396S) and either liprin-α3 or FLAG-tagged Mint-1 were incubated with anti-GFP beads to pull down GFP-CASK and binding partners. To assess Veli interaction, no co-transfection was performed; native Veli was pulled down after incubation of lysates from GFP-CASK-transfected HEK-293 cells with anti-GFP beads to pull down GFP-CASK. Western blots of samples containing whole cell lysate (Input) or immunoprecipitates (Co-IP) were probed with anti-liprin-α3, anti-Veli, or anti-FLAG primary antibodies.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "cask", "xlmr", "mutations", "y268h", "disrupt", "interactions"], "article_id"=>927076, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.g005", "stats"=>{"downloads"=>1, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_CASK_XLMR_mutations_R28L_Y268H_and_P396S_do_not_disrupt_interactions_with_liprin_945_Mint_1_or_Veli_/927076", "title"=>"Functional CASK XLMR mutations (R28L, Y268H and P396S) do not disrupt interactions with liprin-α, Mint-1, or Veli.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377356"], "description"=>"<p>Six hours after transfection, media was exchanged for either fresh media alone or containing 10% glycerol. <i>A.</i> Images, 40X. Insert shows higher magnification. <i>B.</i> Using five representative 20X images (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0088276#pone.0088276.s007\" target=\"_blank\">Figure S7</a>) for each condition, individual cells were classified as free of or containing aggregates in Image J. Bars and error bars represent the average and standard deviation of three independent analyses. * and # indicate statistically significant differences from the wild-type images.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "eliminates", "intracellular"], "article_id"=>927080, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.g006", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Glycerol_treatment_eliminates_intracellular_aggregates_/927080", "title"=>"Glycerol treatment eliminates intracellular aggregates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377357"], "description"=>"<p>For mutations in CaMK domain (R28L and Y268H), the structure 3c0i.pdb was used. For mutations in the SH3-GuK domain (Y728C and W919R), the homology model based on 1 kgd.pdb and 1 kjw.pdb was used. Positive ΔΔG values suggest that the indicated mutation destabilizes CASK’s overall fold.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "mutations"], "article_id"=>927081, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.t002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Predicted_impact_of_mutations_structure_based_/927081", "title"=>"Predicted impact of mutations (structure-based).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377358"], "description"=>"<p>ConSurf conservation scores: 1 (variable) to 9 (highly conserved). Jalview conservation scores: 0 (variable) to 11 (highly conserved). SCPred: residue serves as a stabilization center (“yes”) or not (“no”). N = neutral, P = pathogenic, ? = unclassified. *prediction unreliable at 0.95 probability level.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "mutations"], "article_id"=>927082, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.t001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Predicted_impact_of_mutations_sequence_based_/927082", "title"=>"Predicted impact of mutations (sequence-based).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377363", "https://ndownloader.figshare.com/files/1377364", "https://ndownloader.figshare.com/files/1377365", "https://ndownloader.figshare.com/files/1377366", "https://ndownloader.figshare.com/files/1377367", "https://ndownloader.figshare.com/files/1377368", "https://ndownloader.figshare.com/files/1377369"], "description"=>"<div><p>The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future.</p></div>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "glycerol-induced", "correction", "misfolding", "mutations", "x-linked", "retardation"], "article_id"=>927087, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0088276.s001", "https://dx.doi.org/10.1371/journal.pone.0088276.s002", "https://dx.doi.org/10.1371/journal.pone.0088276.s003", "https://dx.doi.org/10.1371/journal.pone.0088276.s004", "https://dx.doi.org/10.1371/journal.pone.0088276.s005", "https://dx.doi.org/10.1371/journal.pone.0088276.s006", "https://dx.doi.org/10.1371/journal.pone.0088276.s007"], "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_and_Glycerol_Induced_Correction_of_Misfolding_Mutations_in_the_X_Linked_Mental_Retardation_Gene_CASK_/927087", "title"=>"Identification and Glycerol-Induced Correction of Misfolding Mutations in the X-Linked Mental Retardation Gene CASK", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377340"], "description"=>"<p><i>A.</i> Five CASK XLMR mutations are shown in reference to CASK’s domain structure. <i>B.</i> A comparison of the five mutation sites in CASK orthologs from nine species. Conserved residues, white. Residues identical to the mutation, black. Residues that differ from the wild-type and mutant hCASK sequence are gradiently shaded to indicate their similarity to the native hCASK residue.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "cask"], "article_id"=>927064, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.g001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Domain_location_and_conservation_of_five_CASK_mutations_/927064", "title"=>"Domain location and conservation of five CASK mutations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-05 03:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1377346"], "description"=>"<p>Dotted lines indicate contacts. <i>A.</i> CAMK domain of CASK (3c0i.pdb) showing R28 and Y268. <i>B.</i> Native (Arg, cyan) and mutant (Leu, magenta) side-chains at position 28. <i>C.</i> Native (Tyr, cyan) and mutant (His, magenta) side-chains at position 268. <i>D.</i> SH3-GuK domain homology model showing Y728 and W919. SH3 region, yellow. GuK region, pink. <i>E.</i> Native (Tyr, cyan) and mutant (Cys, magenta) side-chains at position 728. <i>F.</i> Native (Trp, cyan) and mutant (Arg, magenta) side-chains at position 919.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "protein structure", "biophysics", "Protein folding", "Computational biology", "Macromolecular structure analysis", "genetics", "Genetic mutation", "Mutational hypotheses", "Human genetics", "Genetic association studies", "Genetics of disease", "Molecular cell biology", "neuroscience", "Mental health", "psychology", "Developmental psychology", "neurology", "Developmental and pediatric neurology", "pediatrics", "modeling", "cask"], "article_id"=>927070, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Leslie E. W. LaConte", "Vrushali Chavan", "Konark Mukherjee"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0088276.g002", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_modeling_of_four_CASK_mutations_/927070", "title"=>"Structural modeling of four CASK mutations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-05 03:24:54"}

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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[282]}, {"subject_area"=>"/Biology and life sciences/Molecular biology", "average_usage"=>[292, 461]}, {"subject_area"=>"/Physical sciences", "average_usage"=>[271]}, {"subject_area"=>"/Physical sciences/Chemistry", "average_usage"=>[262]}]}
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