@article {699, title = {Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0122352}, abstract = {

CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G\>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

}, keywords = {Base Sequence, Calpain, Computational Biology, DNA Primers, Female, Fluorescein Angiography, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Retinal Detachment, Sequence Analysis, DNA, Tomography, Optical Coherence, Uveitis, Vitreoretinopathy, Proliferative}, issn = {1932-6203}, doi = {10.1371/journal.pone.0122352}, author = {Bassuk, Alexander G and Yeh, Steven and Wu, Shu and Martin, Daniel F and Tsang, Stephen H and Gakhar, Lokesh and Mahajan, Vinit B} } @article {115, title = {Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003001}, 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.

}, keywords = {Amino 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}, author = {Mahajan, Vinit B and Skeie, Jessica M and Bassuk, Alexander G and Fingert, John H and Braun, Terry A and Daggett, Heather T and Folk, James C and Sheffield, Val C and Stone, Edwin M} }