Murine model of the Ehlers-Danlos syndrome - col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages
Murine model of the Ehlers-Danlos syndrome - col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages
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DOI：
10.1074/jbc.m511528200
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发表时间：
2006-05-05
影响因子：
4.8
通讯作者：
Birk, DE
中科院分区：
文献类型：
--
作者：
Wenstrup, RJ;Florer, JB;Birk, DE
最常见的引起 Ehlers-Danlos 综合征 (EDS) 经典型的突变会导致 V 型胶原蛋白的前 α1(V) 链单倍体不足，V 型胶原蛋白是一种数量较少的胶原蛋白，与 I 型胶原蛋白共同组装为异型原纤维。为了确定 I/V 型胶原蛋白相互作用在原纤维形成中的作用，并阐明 EDS 中观察到的 V 型胶原蛋白半减少导致异常结缔组织生物发生的机制，我们分析了 col5a1 中靶向失活突变的杂合小鼠，该突变导致 col5a1 mRNA 和胶原蛋白 V 减少 50%。与 EDS 患者相比，他们的主动脉硬度和抗拉强度降低，皮肤过度伸展，正常和正常的抗拉强度均降低。受伤的皮肤。在真皮中，由两个亚群组装的原纤维减少了 50%：相对正常的原纤维，对胶原蛋白 V 具有周期性免疫反应性，其中 I/V 型相互作用调节原纤维组装的成核；以及异常原纤维，缺乏胶原蛋白 V，由 I 型胶原蛋白不受调节的隔离产生。异常原纤维亚群的存在破坏了原纤维融合介导的正常线性和横向生长。因此，异常原纤维成核和功能失调的原纤维生长以及细胞定向原纤维组织的潜在破坏会导致与 EDS 相关的结缔组织功能障碍。
The most commonly identified mutations causing Ehlers-Danlos syndrome (EDS) classic type result in haploinsufficiency of pro alpha 1(V) chains of type V collagen, a quantitatively minor collagen that co-assembles with type I collagen as heterotypic fibrils. To determine the role(s) of type I/V collagen interactions in fibrillogenesis and elucidate the mechanism whereby half-reduction of type V collagen causes abnormal connective tissue biogenesis observed in EDS, we analyzed mice heterozygous for a targeted inactivating mutation in col5a1 that caused 50% reduction in col5a1 mRNA and collagen V. Comparable with EDS patients, they had decreased aortic stiffness and tensile strength and hyperextensible skin with decreased tensile strength of both normal and wounded skin. In dermis, 50% fewer fibrils were assembled with two subpopulations: relatively normal fibrils with periodic immunoreactivity for collagen V where type I/V interactions regulate nucleation of fibril assembly and abnormal fibrils, lacking collagen V, generated by unregulated sequestration of type I collagen. The presence of the aberrant fibril subpopulation disrupts the normal linear and lateral growth mediated by fibril fusion. Therefore, abnormal fibril nucleation and dysfunctional fibril growth with potential disruption of cell-directed fibril organization leads to the connective tissue dysfunction associated with EDS.