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Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.

TitleStructural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.
Publication TypeJournal Article
Year of Publication2015
AuthorsBassuk, Alexander G., Yeh Steven, Wu Shu, Martin Daniel F., Tsang Stephen H., Gakhar Lokesh, and Mahajan Vinit B.
JournalPLoS One
Date Published2015
KeywordsBase 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

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.

Alternate JournalPLoS ONE
PubMed ID25856303
PubMed Central IDPMC4391918
Grant ListR01 EY024665 / EY / NEI NIH HHS / United States
K08EY020530 / EY / NEI NIH HHS / United States
R01EY016822 / EY / NEI NIH HHS / United States