Calpain-5 Mutations Cause Autoimmune Uveitis, Retinal Neovascularization, and Photoreceptor Degeneration

Vinit B Mahajan,Alexander G Bassuk,John H Fingert,Terry A Braun,James C Folk,Jessica M Skeie,Heather T Daggett,Edwin M Stone,Val C Sheffield,Gregory S Barsh

doi:10.1371/journal.pgen.1003001

Vinit B Mahajan, Alexander G Bassuk + Show 8 more

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https://doi.org/10.1371/journal.pgen.1003001

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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.

Highlights

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a heritable autoimmune condition
It is characterized by various stages that mimic several much more common eye diseases, including: uveitis, retinitis pigmentosa, proliferative diabetic retinopathy and proliferative vitreoretinopathy [1,2]
Intraocular fibrosis leads to retinal detachment, similar to that seen in proliferative vitreoretinopathy [9]

Summary

Introduction

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a heritable autoimmune condition. It is characterized by various stages that mimic several much more common eye diseases, including: uveitis, retinitis pigmentosa, proliferative diabetic retinopathy and proliferative vitreoretinopathy [1,2]. Together, these diseases account for a significant fraction of visual morbidity and human blindness [3,4]. Identification of a gene that generates the varied pathological features of these common conditions could have a significant impact on the understanding and treatment of blindness [5]. This combination of overlapping clinical conditions is unusual and suggests that the disease-causing mutations may act through multiple pathways

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