title: Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.
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.
authors: Department of Pediatrics, University of Iowa, Iowa City, IA, United States of America; Omics Lab, University of Iowa, Iowa City, IA, United States of America.
authors: Alexander G
authors: AG
authors: Bassuk
authors: Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, United States of America.
authors: Steven
authors: S
authors: Yeh
authors: Omics Lab, University of Iowa, Iowa City, IA, United States of America.
authors: Shu
authors: S
authors: Wu
authors: Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States of America.
authors: Daniel F
authors: DF
authors: Martin
authors: Bernard & Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Departments of Ophthalmology and Pathology and Cell Biology, Columbia University, New York, NY, United States of America.
authors: Stephen H
authors: SH
authors: Tsang
authors: Department of Biochemistry, University of Iowa, Iowa City, IA, United States of America; Protein Crystallography Facility, University of Iowa, Iowa City, IA, United States of America.
authors: Lokesh
authors: L
authors: Gakhar
authors: Omics Lab, University of Iowa, Iowa City, IA, United States of America; Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States of America.
authors: Vinit B
authors: VB
authors: Mahajan
mesh_terms: D001483:Base Sequence; D002154:Calpain / Q000235:genetics*; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D012163:Retinal Detachment / Q000235:genetics*; D017422:Sequence Analysis, DNA; D041623:Tomography, Optical Coherence; D014605:Uveitis / Q000235:genetics*; D018630:Vitreoretinopathy, Proliferative / Q000235:genetics*
chemical_list: D017931:DNA Primers; D002154:Calpain; C494426:Capn5 protein, human