Calpain-5 Mutations Cause Autoimmune Uveitis, Retinal Neovascularization, and Photoreceptor Degeneration
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{"title"=>"Calpain-5 Mutations Cause Autoimmune Uveitis, Retinal Neovascularization, and Photoreceptor Degeneration", "type"=>"journal", "authors"=>[{"first_name"=>"Vinit B.", "last_name"=>"Mahajan", "scopus_author_id"=>"7102215618"}, {"first_name"=>"Jessica M.", "last_name"=>"Skeie", "scopus_author_id"=>"8863030100"}, {"first_name"=>"Alexander G.", "last_name"=>"Bassuk", "scopus_author_id"=>"6701838698"}, {"first_name"=>"John H.", "last_name"=>"Fingert", "scopus_author_id"=>"6602136038"}, {"first_name"=>"Terry A.", "last_name"=>"Braun", "scopus_author_id"=>"7202108129"}, {"first_name"=>"Heather T.", "last_name"=>"Daggett", "scopus_author_id"=>"15824878900"}, {"first_name"=>"James C.", "last_name"=>"Folk", "scopus_author_id"=>"7102816090"}, {"first_name"=>"Val C.", "last_name"=>"Sheffield", "scopus_author_id"=>"7101844908"}, {"first_name"=>"Edwin M.", "last_name"=>"Stone", "scopus_author_id"=>"7202379334"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-84868119535", "pui"=>"365953660", "pmid"=>"23055945", "issn"=>"15537390", "doi"=>"10.1371/journal.pgen.1003001", "sgr"=>"84868119535"}, "id"=>"07e683e8-9fa5-3cbb-98ce-73fa6fd716a2", "abstract"=>"Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an autoimmune condition of the eye that sequentially mimics uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy as it progresses to complete blindness. We identified two different missense mutations in the CAPN5 gene in three ADNIV kindreds. CAPN5 encodes calpain-5, a calcium-activated cysteine protease that is expressed in retinal photoreceptor cells. Both mutations cause mislocalization from the cell membrane to the cytosol, and structural modeling reveals that both mutations lie within a calcium-sensitive domain near the active site. CAPN5 is only the second member of the large calpain gene family to cause a human Mendelian disorder, and this is the first report of a specific molecular cause for autoimmune eye disease. Further investigation of these mutations is likely to provide insight into the pathophysiologic mechanisms of common diseases ranging from autoimmune disorders to diabetic retinopathy.", "link"=>"http://www.mendeley.com/research/calpain5-mutations-cause-autoimmune-uveitis-retinal-neovascularization-photoreceptor-degeneration", "reader_count"=>21, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>9, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>9, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>2, "Neuroscience"=>1, "Business, Management and Accounting"=>1, "Physics and Astronomy"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Neuroscience"=>{"Neuroscience"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Germany"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/299958", "https://ndownloader.figshare.com/files/300043"], "description"=>"<div><p>Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an autoimmune condition of the eye that sequentially mimics uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy as it progresses to complete blindness. We identified two different missense mutations in the <em>CAPN5</em> gene in three ADNIV kindreds. <em>CAPN5</em> encodes calpain-5, a calcium-activated cysteine protease that is expressed in retinal photoreceptor cells. Both mutations cause mislocalization from the cell membrane to the cytosol, and structural modeling reveals that both mutations lie within a calcium-sensitive domain near the active site. <em>CAPN5</em> is only the second member of the large calpain gene family to cause a human Mendelian disorder, and this is the first report of a specific molecular cause for autoimmune eye disease. Further investigation of these mutations is likely to provide insight into the pathophysiologic mechanisms of common diseases ranging from autoimmune disorders to diabetic retinopathy.</p> </div>", "links"=>[], "tags"=>["calpain-5", "mutations", "autoimmune", "retinal", "photoreceptor", "degeneration"], "article_id"=>119145, "categories"=>["Genetics", "Medicine"], "users"=>["Vinit B. Mahajan", "Jessica M. Skeie", "Alexander G. Bassuk", "John H. Fingert", "Terry A. Braun", "Heather T. Daggett", "James C. Folk", "Val C. Sheffield", "Edwin M. Stone"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003001.s001", "https://dx.doi.org/10.1371/journal.pgen.1003001.s002"], "stats"=>{"downloads"=>1, "page_views"=>54, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Calpain_5_Mutations_Cause_Autoimmune_Uveitis_Retinal_Neovascularization_and_Photoreceptor_Degeneration/119145", "title"=>"Calpain-5 Mutations Cause Autoimmune Uveitis, Retinal Neovascularization, and Photoreceptor Degeneration", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-10-04 02:32:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/563782"], "description"=>"<p>A–B. Clusters of autoimmune reactive leukocytes are visible in the vitreous cavity (inset, arrows). C. Electroretinography shows loss of the b-wave. D. Fundus image of the normal retina. E. Fundus image of the ADNIV retina shows pigmentary degeneration (arrow) similar to retinitis pigmentosa. F. Fluorescein angiography reveals cystoid macular edema at the fovea (arrow), a consequence of autoimmune intraocular inflammation. G. Preretinal fibrosis leads to tractional retinal detachments. H. Vitreous hemorrhage (arrow) from retinal neovascularization. I. Phthisis bulbi and involution of eye tissues in end-stage ADNIV.</p>", "links"=>[], "tags"=>["genetics and genomics", "ophthalmology"], "article_id"=>234275, "categories"=>["Genetics", "Medicine"], "users"=>["Vinit B. Mahajan", "Jessica M. Skeie", "Alexander G. Bassuk", "John H. Fingert", "Terry A. Braun", "Heather T. Daggett", "James C. Folk", "Val C. Sheffield", "Edwin M. Stone"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003001.g001", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ADNIV_phenotype_/234275", "title"=>"ADNIV phenotype.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:11:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/564376"], "description"=>"<p>A. No significant signal was detected in control retinal sections probed with secondary antibody or primary antibody blocked with recombinant calpain-5. DAPI highlights the cell nuclei (blue) B. Calpain-5 was detected in photoreceptor cells (green). A punctate expression pattern was most prominent overlying the photoreceptor nuclei in the outer nuclear layer (ONL) and inner and outer segments (IS, OS). C. Anti-myc antibody western blot detects a single species (black arrow) of the appropriate size in HEK293T cells transfected with a vector bearing normal, myc-tagged <i>CAPN5</i>. D. No significant anti-myc signal was detected in the nuclei (white arrowhead) or cytoplasm (white arrow) of control cells that were treated with transfection reagent alone, vector alone, or secondary antibody alone. E. Anti-myc antibody shows that calpain-5 (green) is expressed in a ruffled pattern (white arrow) that obscures the underlying nuclei (white arrowhead) suggesting a location near the cell surface in these very thin cultured cells. F. Transfection with a mutant <i>CAPN5</i> (Arg243Leu) exhibits a more uniform anti-myc signal that does not obscure the nuclei (white arrowhead) and is thus more compatible with localization to the cytoplasm (white arrow).</p>", "links"=>[], "tags"=>["retinal", "photoreceptor", "cells", "cultured"], "article_id"=>234859, "categories"=>["Genetics", "Medicine"], "users"=>["Vinit B. Mahajan", "Jessica M. Skeie", "Alexander G. Bassuk", "John H. Fingert", "Terry A. Braun", "Heather T. Daggett", "James C. Folk", "Val C. Sheffield", "Edwin M. Stone"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003001.g005", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Calpain_5_expression_in_human_retinal_photoreceptor_cells_and_cultured_cells_/234859", "title"=>"Calpain-5 expression in human retinal photoreceptor cells and cultured cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:20:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/564038"], "description"=>"<p>A. The ADNIV locus was previously mapped to chromosome 11q13 (green bar). STRP and SNP array mapping narrowed the interval (red bar). B. <i>CAPN5</i> gene structure is composed of 13 exons. C. Chromatogram of normal <i>CAPN5</i> DNA sequence in exon 6. D–E. Chromatograms of ADNIV subjects shows mutations in <i>CAPN5</i> exon 6. F. SSCP distinguishes between normal sequence and ADNIV mutations.</p>", "links"=>[], "tags"=>["harbors", "mutations", "exon", "adniv"], "article_id"=>234520, "categories"=>["Genetics", "Medicine"], "users"=>["Vinit B. Mahajan", "Jessica M. Skeie", "Alexander G. Bassuk", "John H. Fingert", "Terry A. Braun", "Heather T. Daggett", "James C. Folk", "Val C. Sheffield", "Edwin M. Stone"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003001.g003", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_CAPN5_gene_harbors_mutations_in_exon_6_of_ADNIV_subjects_/234520", "title"=>"The <i>CAPN5</i> gene harbors mutations in exon 6 of ADNIV subjects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:15:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/564194"], "description"=>"<p>A. Both ADNIV mutations (red arrows) are located in exon 6, which encodes a portion of the catalytic domain and two of three catalytic residues (blue arrows). Primary protein sequence analysis shows the ADNIV-1/2 and ADNIV-3 mutations to be 8–9 amino acids upstream of the catalytic histidine residue. Secondary structure modeling shows that the two mutations are within a putative alpha helical domain. One mutated codon results in the loss of a basic residue, while the other introduces a proline into the putative alpha helix. B. Alignment of calpain-5 orthologs shows very high evolutionary conservation of the mutated residues (red arrows). Amino acid mismatches are color-highlighted. C. Twelve human calpain paralogs show significant differences in exon 6 (Black, 100% similarity; Dark grey, 80–100% similarity; Light grey, 60–80% similarity; White, less than 60% similarity). D. Three-dimensional modeling of the catalytic domain shows the location of the active site cleft (red outline). E. Magnified view of the active site cleft shows the catalytic triad (dashed line – blue text) and location of the two mutations (red arrows and text). Both mutations are located within a peptide loop that is homologous to a flexible loop of calpain-1 that undergoes a calcium-induced conformational change in association with regulation of the active site cleft (see text).</p>", "links"=>[], "tags"=>["modeling", "calpain-5", "adniv"], "article_id"=>234678, "categories"=>["Genetics", "Medicine"], "users"=>["Vinit B. Mahajan", "Jessica M. Skeie", "Alexander G. Bassuk", "John H. Fingert", "Terry A. Braun", "Heather T. Daggett", "James C. Folk", "Val C. Sheffield", "Edwin M. Stone"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003001.g004", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Protein_structure_modeling_of_calpain_5_and_ADNIV_mutants_/234678", "title"=>"Protein structure modeling of calpain-5 and ADNIV mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:17:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/563883"], "description"=>"<p>A–C. Three families with clinical features of ADNIV exhibit a dominant pattern of inheritance. Black symbols represent clinically affected subjects. Open symbols represent unaffected subjects. Deceased individuals are marked by a slash.</p>", "links"=>[], "tags"=>["genetics and genomics", "ophthalmology"], "article_id"=>234372, "categories"=>["Genetics", "Medicine"], "users"=>["Vinit B. Mahajan", "Jessica M. Skeie", "Alexander G. Bassuk", "John H. Fingert", "Terry A. Braun", "Heather T. Daggett", "James C. Folk", "Val C. Sheffield", "Edwin M. Stone"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003001.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ADNIV_pedigrees_/234372", "title"=>"ADNIV pedigrees.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:12:52"}

PMC Usage Stats | Further Information

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Relative Metric

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