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Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.

TitleCalpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.
Publication TypeJournal Article
Year of Publication2012
AuthorsMahajan, Vinit B., Skeie Jessica M., Bassuk Alexander G., Fingert John H., Braun Terry A., Daggett Heather T., Folk James C., Sheffield Val C., and Stone Edwin M.
JournalPLoS Genet
Volume8
Issue10
Paginatione1003001
Date Published2012
KeywordsAmino Acid Sequence, Base Sequence, Calpain, Cell Line, Cells, Cultured, Choroid Diseases, Exome, Exons, Eye Diseases, Hereditary, Female, Gene Expression, Genetic Linkage, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Photoreceptor Cells, Vertebrate, Protein Conformation, Protein Transport, Retinal Degeneration, Sequence Alignment
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.

Alternate JournalPLoS Genet.