Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.
Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.
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DOI：
10.1371/journal.pgen.1003001
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Stone EM
中科院分区：
文献类型：
--
作者：
Mahajan VB;Skeie JM;Bassuk AG;Fingert JH;Braun TA;Daggett HT;Folk JC;Sheffield VC;Stone EM
常染色体显性遗传性新生血管炎性玻璃体视网膜病变（ADNIV）是一种眼部自身免疫性疾病，随着其进展至完全失明，依次模仿葡萄膜炎、色素性视网膜炎和增殖性糖尿病视网膜病变。我们在三种ADNIV激酶中发现了CAPN 5基因的两种不同错义突变。CAPN 5编码钙蛋白酶-5，一种在视网膜感光细胞中表达的钙激活半胱氨酸蛋白酶。这两种突变导致从细胞膜到胞质溶胶的错误定位，并且结构建模揭示这两种突变位于活性位点附近的钙敏感域内。CAPN 5是导致人类孟德尔疾病的大钙蛋白酶基因家族的第二个成员，这是第一次报道自身免疫性眼病的特定分子原因。对这些突变的进一步研究可能会为从自身免疫性疾病到糖尿病视网膜病变等常见疾病的病理生理机制提供深入了解。我们照顾几个家庭与遗传形式的自身免疫性炎症内的眼睛。患者还会出现出血、疤痕组织，最终失明。利用先进的基因分析方法，我们发现这种疾病的原因是CAPN 5基因的基因突变。这个基因产生一种蛋白质，calpain-5，它属于钙激活酶家族，可以切割细胞内的其他蛋白质。钙蛋白酶-5在视网膜中表达，疾病突变改变了它在细胞内的位置。未来的研究，以了解这种蛋白质如何导致炎症和出血内的眼睛将有助于我们开发治疗这种情况和更常见的眼睛疾病与炎症和出血。
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. We care for several families with an inherited form of autoimmune inflammation inside the eye. The patients also develop bleeding, scar tissue, and eventually blindness. Using advanced gene analysis methods, we discovered the cause of this disease is gene mutations in the CAPN5 gene. This gene makes a protein, calpain-5, which belongs to a family of calcium-activated enzymes that slice other proteins inside cells. Calpain-5 is expressed in the retina, and the disease mutations alter its location inside the cell. Future studies to understand how this protein causes inflammation and bleeding inside the eye will help us develop treatments for this condition and more common eye diseases with inflammation and bleeding.
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影响因子：
11.2
作者：
Krahn, Martin;Lopez de Munain, Adolfo;Levy, Nicolas
通讯作者：
Levy, Nicolas
影响因子：
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Serrano-Rios, Manuel
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17.8
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通讯作者：
Neidhardt, John