Shu Xinhua, Tulloch Brian, Lennon Alan, Vlachantoni Dafni, Zhou Xinzhi, Hayward Caroline, Wright Alan F
MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
Hum Mol Genet. 2006 May 15;15(10):1680-9. doi: 10.1093/hmg/ddl091. Epub 2006 Apr 6.
Late-onset retinal macular degeneration (L-ORMD) is an autosomal dominant condition resembling age-related macular degeneration (AMD) in which a key pathological feature is a thick extracellular sub-retinal pigment epithelial (RPE) deposit. L-ORMD is caused by mutation in the C1QTNF5 (CTRP5) short-chain collagen gene, but the disease mechanism is unknown. Here, we first show that wild-type C1QTNF5 is secreted, whereas mutant C1QTNF5 is misfolded and retained within the endoplasmic reticulum (ER). Secondly, the ER retained mutant protein has a shorter half-life than wild-type C1QTNF5 and is preferentially degraded by proteasomes. Thirdly, C1QTNF5 is shown to interact with the membrane-type frizzled related protein (MFRP), on the basis of yeast two-hybrid, protein pull-down and co-immunoprecipitation assays and RPE co-localization. These data suggest that L-ORMD is due to insufficient levels of secreted C1QTNF5, compromised RPE cell function resulting from ER retention of the mutant protein or both mechanisms.
迟发性视网膜黄斑变性（L-ORMD）是一种常染色体显性疾病，类似于年龄相关性黄斑变性（AMD），其关键病理特征是视网膜色素上皮（RPE）下存在厚厚的细胞外沉积物。L-ORMD由C1QTNF5（CTRP5）短链胶原基因突变引起，但疾病机制尚不清楚。在此，我们首先表明野生型C1QTNF5是可分泌的，而突变型C1QTNF5发生错误折叠并保留在内质网（ER）中。其次，内质网保留的突变蛋白半衰期比野生型C1QTNF5短，且优先被蛋白酶体降解。第三，基于酵母双杂交、蛋白质下拉和免疫共沉淀实验以及RPE共定位，表明C1QTNF5与膜型卷曲相关蛋白（MFRP）相互作用。这些数据表明，L-ORMD是由于分泌的C1QTNF5水平不足、突变蛋白在内质网滞留导致RPE细胞功能受损或两者兼而有之。
