Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation
Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation
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DOI：
10.1093/hmg/ddv399
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发表时间：
2015-12-15
影响因子：
3.5
通讯作者：
Nishina, Patsy M.
中科院分区：
文献类型：
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作者：
Collin, Gayle B.;Hubmacher, Dirk;Nishina, Patsy M.
人类基因突变揭示了大量ADAMTS（具有血小板反应蛋白1型基序的去整合素样和金属蛋白酶（replysin型））蛋白对于正常的眼发育和眼功能是必需的。人类ADAMTSL 4编码一种与晶状体微纤维生物发生有关的ADAMTS样蛋白，其突变可引起晶状体异位（EL）和EL et pupillae。在这里，我们报告了第一个ADAMTSL 4小鼠模型，tvrm267，在Adamtsl4中携带无义突变。纯合子Adamts14（tvrm267）小鼠重现了在人类中观察到的EL表型，我们的分析强烈表明，ADAMTSL 4是小带纤维稳定锚定到透镜囊所必需的。出乎意料的是，纯合子Adamts14（tvrm267）小鼠主要在下眼中表现出局灶性视网膜色素上皮（RPE）缺陷。色素沉着减少、细胞形态改变和RPE特异性转录物减少表明RPE去分化。最后，与ADAMTSL 4突变患者的一个子集一样，观察到相对于年龄匹配的对照组，眼轴长度增加，并且与RPE表型的严重程度相关。总之，Adamtsl4（tvrm267）模型提供了一个有价值的工具，以进一步阐明悬韧带形成的分子基础、EL的病理生理学和ADAMTSL 4在维持RPE中的功能。
Human gene mutations have revealed that a significant number of ADAMTS (a disintegrin-like and metalloproteinase (reprolysin type) with thrombospondin type 1 motifs) proteins are necessary for normal ocular development and eye function. Mutations in human ADAMTSL4, encoding an ADAMTS-like protein which has been implicated in fibrillin microfibril biogenesis, cause ectopia lentis (EL) and EL et pupillae. Here, we report the first ADAMTSL4 mouse model, tvrm267, bearing a nonsense mutation in Adamtsl4. Homozygous Adamtsl4(tvrm267) mice recapitulate the EL phenotype observed in humans, and our analysis strongly suggests that ADAMTSL4 is required for stable anchorage of zonule fibers to the lens capsule. Unexpectedly, homozygous Adamtsl4(tvrm267) mice exhibit focal retinal pigment epithelium (RPE) defects primarily in the inferior eye. RPE dedifferentiation was indicated by reduced pigmentation, altered cellular morphology and a reduction in RPE-specific transcripts. Finally, as with a subset of patients with ADAMTSL4 mutations, increased axial length, relative to age-matched controls, was observed and was associated with the severity of the RPE phenotype. In summary, the Adamtsl4(tvrm267) model provides a valuable tool to further elucidate the molecular basis of zonule formation, the pathophysiology of EL and ADAMTSL4 function in the maintenance of the RPE.