Fuchs corneal dystrophy:: Aberrant collagen distribution in an L450W mutant of the COL8A2 gene
Fuchs corneal dystrophy:: Aberrant collagen distribution in an L450W mutant of the COL8A2 gene
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DOI：
10.1167/iovs.05-0497
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Green, WR
中科院分区：
文献类型：
--
作者：
Gottsch, JD;Zhang, C;Green, WR
目的。对早发性 Fuchs 角膜营养不良 (FCD) COL8A2 突变体的后弹力层进行组织学表征，并将这些结果与晚发性 FCD 角膜和正常角膜进行比较。使用 IV 型胶原、VIIIA1 型、VIIIA2 型、纤连蛋白和层粘连蛋白抗体对 L450W COL8A2 突变患者和其他晚发性疾病患者的角膜外植体进行了研究。对一部分外植体进行透射电子显微镜检查。对照外植体包括没有已知疾病的眼库角膜和来自不相关病症的手术外植体。结果。在正常角膜中，在后弹力层前半部观察到共定位的 COL8A1 和 COL8A2 的规则阵列。在 L450W 突变体中，后弹力层的膜比正常细胞厚几倍，并被 COL8A2 染色强烈的折射链和泡穿过，这一特征在晚发 FCD 中也观察到。在后弹力层前缘观察到 VIII 型胶原蛋白的 α1 和 α2 亚型均呈高水平，这是晚发 FCD 中也发现的另一个异常特征。 L450W 角膜的超微结构显示，前带状层结构良好，比正常角膜厚三倍多。不寻常的薄内层富含宽间隔的胶原蛋白斑块。该层是一种与 FCD 相关的独特病理结构，其特征在于类似于 120 nm 的周期性和 VIII 型胶原蛋白的存在。后弹力层中胶原蛋白 IV、纤连蛋白和层粘连蛋白的沉积也大大增加，这是早发型和晚发型疾病共有的另一个普遍特征。结论。早发性 COL8A2 L450W 疾病涉及后弹力层内 VIII 型胶原蛋白的大量积累和异常组装，这一过程被认为在胎儿发育期间开始。 FCD 的早发型和晚发型亚型似乎都是基底膜组装异常的结果，而不是内皮代谢的主要缺陷。
PURPOSE. To characterize histologically Descemet's membrane in an early-onset Fuchs corneal dystrophy (FCD) COL8A2 mutant and compare these findings with corneas from late-onset FCD and normal corneas.METHODS. A corneal explant from a patient with the L450W COL8A2 mutation and others with late-onset disease were studied with antibodies to collagens IV, VIIIA1, VIIIA2, fibronectin, and laminin. Transmission electron microscopy was performed on a portion of the explant. Control explants included eye bank corneas without known disease and surgical explants from unrelated conditions.RESULTS. In normal corneas, a regular array of colocalized COL8A1 and COL8A2 was observed in the anterior half of Descemet's membrane. In the L450W mutant, Descemet's membrane was several times thicker than normal and traversed by refractile strands and blebs that stained intensely for COL8A2, a feature also observed in late-onset FCD. Both the alpha 1 and alpha 2 subtypes of collagen VIII were observed at high levels along the anterior edge of Descemet's, another abnormal feature also found in late-onset FCD. Ultrastructure of the L450W cornea revealed a well-formed anterior banded layer more than three times thicker than normal. An unusual, thin internal layer was rich in patches of wide-spaced collagen. The layer is a distinctive pathologic structure that is associated with FCD and is characterized by similar to 120 nm periodicity and the presence of collagen VIII. Depositions of collagen IV, fibronectin, and laminin were also greatly increased in the of posterior Descemet's membrane, yet another general feature shared between early- and late-onset disease.CONCLUSIONS. Early-onset COL8A2 L450W disease involves massive accumulation and abnormal assembly of collagen VIII within Descemet's membrane, a process that is presumed to begin during fetal development. Both early- and late-onset subtypes of FCD appear to be the result of abnormal basement membrane assembly rather than a primary defect in endothelial metabolism.