Geleophysic dysplasia is a rare, frequently lethal condition characterized by severe short stature with progressive joint contractures, cardiac, pulmonary, and skin anomalies. Geleophysic dysplasia results from dominant fibrillin-1 (FBN1) or recessive ADAMTSL2 mutations, suggesting a functional link between ADAMTSL2 and fibrillin microfibrils. Mice lacking ADAMTSL2 die at birth, which has precluded analysis of postnatal limb development and mechanisms underlying the skeletal anomalies of geleophysic dysplasia. Here, detailed expression analysis of Adamtsl2 using an intragenic lacZ reporter shows strong Adamtsl2 expression in limb tendons. Expression in developing and growing bones is present in regions that are destined to become articular cartilage but is absent in growth plate cartilage. Consistent with strong tendon expression, Adamtsl2 conditional deletion in limb mesenchyme using Prx1-Cre led to tendon anomalies, albeit with normal collagen fibrils, and distal limb shortening, providing a mouse model for geleophysic dysplasia. Unexpectedly, conditional Adamtsl2 deletion using Scx-Cre, a tendon-specific Cre-deleter strain, which does not delete in cartilage, also impaired skeletal growth. Recombinant ADAMTSL2 is shown here to colocalize with fibrillin microfibrils in vitro, and enhanced staining of fibrillin-1 microfibrils was observed in Prx1-Cre Adamtsl2 tendons. The findings show that ADAMTSL2 specifically regulates microfibril assembly in tendons and that proper microfibril composition in tendons is necessary for tendon growth. We speculate that reduced bone growth in geleophysic dysplasia may result from external tethering by short tendons rather than intrinsic growth plate anomalies. Taken together with previous work, we suggest that GD results from abnormal microfibril assembly in tissues, and that ADAMTSL2 may limit the assembly of fibrillin microfibrils.

中文翻译：

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肢体和肌腱特异性Adamtsl2缺失确定了ADAMTSL2在小鼠胶体发育异常模型中的肌腱生长中的作用。

凝胶体发育异常是一种罕见的，经常致死的疾病，其特征是身材矮小严重，伴有进行性关节挛缩，心脏，肺部和皮肤异常。介导的原纤维蛋白-1（FBN1）或隐性ADAMTSL2突变可导致凝胶体发育异常，提示ADAMTSL2和原纤维微纤维之间存在功能性联系。缺少ADAMTSL2的小鼠在出生时死亡，这已排除了对产后肢体发育和胶体发育异常骨骼异常的潜在机制的分析。在这里，使用基因内lacZ报告基因对Adamtsl2进行的详细表达分析表明，Adamtsl2在肢体肌腱中表达强。在发育中和生长中的骨骼中存在表达，这些区域注定会变成关节软骨，但在生长板软骨中却不存在。与强筋腱表达相一致，Adamtsl2使用Prx1-Cre进行肢体间充质的条件性缺失会导致肌腱异常，尽管胶原纤维正常，并且肢体远端缩短，为小鼠胶体发育异常提供了模型。出乎意料的是，使用Scx-Cre（一种腱特异的Cre-deleter菌株）进行条件性的Adamtsl2缺失，也不会在软骨中缺失，这也损害了骨骼的生长。重组ADAMTSL2在此处显示与原纤维微丝原纤维共定位，并且在Prx1-Cre Adamtsl2肌腱中观察到原纤维-1微丝的染色增强。研究结果表明，ADAMTSL2特异性调节肌腱中的微纤维组装，并且肌腱中适当的微纤维组成对于肌腱生长是必不可少的。我们推测，骨骼肌发育异常的骨生长减少可能是由于短肌腱的外部束缚而不是固有的生长板异常所致。结合以前的工作，我们建议GD是由组织中微纤丝的异常组装引起的，而ADAMTSL2可能会限制纤丝蛋白微纤丝的组装。