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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome
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Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome

机译：突变型核纤层蛋白A的积累导致Hutchinson-Gilford早衰综合征的核结构逐步改变

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摘要

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LADelta50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LADelta50. Introduction of LADelta50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LADelta50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.
机译：Hutchinson-Gilford早衰综合症（HGPS）是一种过早的衰老疾病，通常是由lamin A基因的点突变引起的，导致该蛋白在C末端附近缺乏50aa的蛋白质，表示为LADelta50。在这里，我们通过光镜和电子显微镜显示，HGPS与核形状的重大变化有关，包括核包膜的叶状化，核层的增厚，周围异染色质的丢失和核孔的聚集。随着HGPS细胞在培养物中的老化，这些结构缺陷会恶化，其严重程度与LADelta50的明显增加有关。通过转染或蛋白质注射将LADelta50引入正常细胞会引起相同的变化。我们假设核结构的这些变化是由于LADelta50的浓度依赖性显性负效应，导致破坏了与层蛋白相关的功能，从维持核形状到调节基因表达和DNA复制。

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