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首页> 外文期刊>Nucleus >Amphibian oocyte nuclei expressing lamin progeria the progea mutation E145K exhibit an increased elastic modulus
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Amphibian oocyte nuclei expressing lamin progeria the progea mutation E145K exhibit an increased elastic modulus

机译：表达lamin早衰的两栖卵母细胞核，前突突变E145K表现出增加的弹性模量

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摘要

Mutations in the human lamin A gene (LMNA) cause a wide range of diseases (laminopathies). Among these is the Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease. Most HGPS patients carry a silent point mutation, which activates a cryptic splice site resulting in the expression of a permanently isoprenylated and truncated lamin AΔ50/progerin. Another type of mutant lamin A namely, E145K-lamin A, also causes HGPS. E145K-lamin A induces profound changes in the nuclear architecture of patient cells as well as after expression in cultured cells. The E145K mutation is located in the (a-helical central domain of lamin A, which is involved in lamin filament assembly. In vitro analyses of purified E145K-lamin A have revealed severe assembly defects into higher order lamin structures, which indicates an abnormal lateral association of protofilaments. To analyze how the altered assembly observed in vitro might influence the mechanics of a nuclear lamina formed by E145K-lamin A, mutant and wild type lamin A were ectopically expressed in amphibian oocytes. Both types form a lamina consisting of multi-layered sheets of filaments at the inner side of the nuclear envelope. The mechanical proper-ties of isolated nuclei were measured by atomic force microscopy (AFM). From the resulting force curves, the stiffness of the lamina was estimated. The thickness of the resulting lamin A layer was then measured by TEM. The two parameters allowed us to estimate the elastic modulus (Young's modulus) of the lamina. Lamin A sheets made from E145K filaments have a higher Young's modulus compared to wild type filaments, i.e., the E145K-lamin A sheets are more rigid than wild type lamina of comparable thickness.
机译：人层粘连蛋白A基因（LMNA）中的突变会引起多种疾病（拉丁病）。其中包括Hutchinson-Gilford早衰综合症（HGPS），这是一种罕见的过早衰老疾病。大多数HGPS患者携带一个沉默点突变，该突变激活了一个隐秘的剪接位点，导致永久性异戊二烯基化和截短的laminAΔ50/ progerin的表达。突变型lamin A的另一种类型，即E145K-lamin A，也会引起HGPS。 E145K-lamin A诱导患者细胞的核结构以及在培养细胞中表达后发生深刻变化。 E145K突变位于（lamin A的a螺旋中央结构域，与lamin细丝组装有关。体外分析纯化​​的E145K-lamin A时发现严重的组装缺陷变成了高级的lamin结构，这表明侧向异常为了分析体外观察到的装配改变如何影响由E145K-lamin A形成的核层的力学，两栖类卵母细胞中异位表达了突变型和野生型层蛋白A，这两种类型都形成了由多个核壳内侧的层状细丝层，通过原子力显微镜（AFM）测量孤立核的机械性质，从所得的力曲线中估算出层的刚度，所得层的厚度然后用TEM测量lamin A层，这两个参数使我们能够估计层板的弹性模量（杨氏模量）。与野生型丝相比，它们具有更高的杨氏模量，即，E145K-lamin A片材比具有相同厚度的野生型层片更坚硬。

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