An alpha 2 collagen VIII transgenic knock-in mouse model of Fuchs endothelial corneal dystrophy shows early endothelial cell unfolded protein response and apoptosis
An alpha 2 collagen VIII transgenic knock-in mouse model of Fuchs endothelial corneal dystrophy shows early endothelial cell unfolded protein response and apoptosis
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DOI：
10.1093/hmg/ddr473
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发表时间：
2012-01-15
影响因子：
3.5
通讯作者：
Kimos, Martha
中科院分区：
文献类型：
--
作者：
Jun, Albert S.;Meng, Huan;Kimos, Martha
Fuchs角膜内皮营养不良（FECD）是角膜移植的主要适应症。FECD的特征在于内皮细胞形态的进行性改变、内皮基底膜的赘生物（滴状物）和增厚以及细胞死亡。最终，这些变化会导致角膜水肿和视力丧失。由于在早期疾病阶段缺乏视力丧失和数十年的病程，FECD的早期病理生理学几乎是未知的，因为病理组织的研究仅限于移植时获得的终末期组织。显示引起FECD的第一个遗传缺陷是点突变，其引起α 2胶原蛋白8基因（COL 8A 2）中氨基酸位置455（Q455 K）处的谷氨酰胺至赖氨酸的取代，这导致该疾病的早发形式。具有该突变的纯合突变体敲入小鼠（Col 8a 2（Q455 K/Q455 K））显示出与人类疾病惊人相似的特征，包括内皮细胞形态、细胞损失和基底膜滴的进行性改变。超微结构分析显示主要缺陷为扩张的内质网（ER），提示ER应激和未折叠蛋白反应（UPR）激活。免疫组化、蛋白质印迹、定量逆转录聚合酶链反应和末端脱氧核苷酸转移酶2-脱氧尿苷、5-三磷酸缺口末端标记分析支持Col 8a 2（Q455 K/Q455 K）突变角膜内皮中UPR激活和UPR相关凋亡。该研究证实了COL 8A 2基因中的Q455 K取代足以在该疾病的第一小鼠模型中引起FECD，并支持UPR和UPR相关的细胞凋亡在COL 8A 2突变引起的FECD发病机制中的作用。
Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation. FECD is characterized by progressive alterations in endothelial cell morphology, excrescences (guttae) and thickening of the endothelial basement membrane and cell death. Ultimately, these changes lead to corneal edema and vision loss. Due to the lack of vision loss in early disease stages and the decades long disease course, early pathophysiology in FECD is virtually unknown as studies of pathologic tissues have been limited to end-stage tissues obtained at transplant. The first genetic defect shown to cause FECD was a point mutation causing a glutamine to lysine substitution at amino acid position 455 (Q455K) in the alpha 2 collagen 8 gene (COL8A2) which results in an early onset form of the disease. Homozygous mutant knock-in mice with this mutation (Col8a2(Q455K/Q455K)) show features strikingly similar to human disease, including progressive alterations in endothelial cell morphology, cell loss and basement membrane guttae. Ultrastructural analysis shows the predominant defect as dilated endoplasmic reticulum (ER), suggesting ER stress and unfolded protein response (UPR) activation. Immunohistochemistry, western blotting, quantitative reverse transcriptase polymerase chain reaction and terminal deoxynucleotidyl transferase 2-deoxyuridine, 5-triphosphate nick end-labeling analyses support UPR activation and UPR-associated apoptosis in the Col8a2(Q455K/Q455K) mutant corneal endothelium. This study confirms the Q455K substitution in the COL8A2 gene as being sufficient to cause FECD in the first mouse model of this disease and supports the role of the UPR and UPR-associated apoptosis in the pathogenesis of FECD caused by COL8A2 mutations.