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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells
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A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells

机译：在Hutchinson-Gilford早衰综合征中过表达的Lamin A蛋白同工型干扰早衰和正常细胞中的有丝分裂

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摘要

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C → T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed "progerin/ LAΔ50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LAΔ50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LAΔ50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LAΔ50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LAΔ50. Furthermore, we demonstrate that small amounts of progerin/LAΔ50 exist in normal fibroblasts, and a significant percentage of these progerin/ LAΔ50-expressing normal cells are binucleated, implicating progerin/LAΔ50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.
机译：Hutchinson-Gilford早衰综合症（HGPS）是一种罕见的遗传性疾病，其特征是过早衰老。经典的HGPS是由LMNA基因的第11外显子从头突变（残基1824，C→T）引起的，它激活了一个隐秘的剪接供体，并导致了一种称为“ progerin /LAΔ50”的突变型层粘蛋白A（LA）蛋白，该蛋白缺乏正常的切割位点去除C末端的法呢基。在相间期，不可逆的法尼基化的早老蛋白/LAΔ50锚定在核膜上，并引起特征性的核起泡。然而，Progerin /LAΔ50在有丝分裂期间的定位和行为是完全未知的。在这里，我们报道在有丝分裂过程中，progerin /LAΔ50错位成不可溶的细胞质聚集体和膜，并导致异常的染色体分离和双核化。这些表型可通过法呢基转移酶抑制剂或不适合法尼基化的突变体progerin /LAΔ50来挽救。此外，我们证明了正常成纤维细胞中存在少量的progerin /LAΔ50，并且这些表达progerin /LAΔ50的正常细胞中有很大百分比是双核的，这暗示progerin /LAΔ50在正常衰老过程中会引起类似的有丝分裂缺陷。我们的发现提供了HGPS中有丝分裂异常的证据，并可能揭示了一般的衰老现象。

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