Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells
Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells
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DOI：
10.1093/hmg/ddi385
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发表时间：
2005-12-01
影响因子：
3.5
通讯作者：
Barker, MD
中科院分区：
文献类型：
--
作者：
Langton, KP;McKie, N;Barker, MD
Sorsby眼底营养不良（SFD）是一种常染色体显性视网膜变性疾病，由金属蛋白酶组织抑制剂-3（TIMP-3）基因外显子5突变引起。这些突变引起疾病表型的机制尚不清楚。在试图确定这些分子的共同特性，可能是疾病表型的基础，一系列的SFD突变体从人视网膜色素上皮（RPE）细胞表达。这表明分子间二硫键形成导致的周转抗性是所有检查的SFD突变体的共同特性，为SFD患者眼中观察到的蛋白质沉积增加提供了可能的解释。相比之下，SFD突变体在抑制基质金属蛋白酶-2（MMP-2）（一种有效的血管生成介质）细胞表面活化的能力方面存在差异，范围从完全活性到完全失活。这些数据表明，增加沉积的活性TIMP-3，而不是失调的金属蛋白酶抑制，可能是主要的，在SFD的起始事件。
Sorsby's fundus dystrophy (SFD) is an autosomal dominant degenerative disease of the retina, caused by mutations in exon 5 of the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). The mechanism by which these mutations give rise to the disease phenotype is unknown. In an attempt to identify common properties of these molecules that might underlie the disease phenotype, a range of SFD mutants were expressed from human retinal pigment epithelial (RPE) cells. This showed that resistance to turnover, resulting from intermolecular disulfide bond formation, was a common property of all the SFD mutants examined, providing a possible explanation for the increased deposition of the protein observed in eyes from SFD patients. In contrast, SFD mutants varied in their ability to inhibit cell-surface activation of matrix metalloproteinase-2 (MMP-2), a potent mediator of angiogenesis, ranging from being fully active to totally inactive. These data show that increased deposition of active TIMP-3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary, initiating event in SFD.