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.
Highlights
Mendelian forms of autoimmune disease are rare
The proband (II:1) was a 26 year-old female who began to lose vision at age 23. She was diagnosed with noninfectious uveitis with recurrent cystoid macular edema (CME) OU
Over the six years, she underwent several surgeries in both eyes. These included fluocinolone acetonide (FA) implantation OU for her uveitis and CME, phacoemulsification and intraocular lens implantation for cataracts, Ahmed tube shunts for steroidresponse glaucoma, and vitrectomies for vitreomacular traction and epiretinal membranes
Summary
In two large, unrelated kindreds we recently identified the first mutation shown to cause nonsyndromic uveitis: coding mutations in CAPN5 caused an inherited uveitis called autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM #602537) [1]. CAPN5 encodes calpain-5, a calcium-activated signaling protease expressed by retinal photoreceptors [1]. ADNIV-associated mutations in calpain-5 reside in a flexible loop gating the active site and are expected to alter enzymatic activity, likely leading to a gain of function [1]. For calpains in general, excess activity is associated with retinal and cell degeneration [2,3,4]. We identify a new CAPN5 mutation in a third ADNIV family and model the functional effect of this mutation on the protein structure
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