Cao Kan, Capell Brian C, Erdos Michael R, Djabali Karima, Collins Francis S
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4949-54. doi: 10.1073/pnas.0611640104. Epub 2007 Mar 14.
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/LADelta50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LADelta50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LADelta50 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/LADelta50. Furthermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleated, implicating progerin/LADelta50 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.
哈钦森 - 吉尔福德早衰综合征（HGPS）是一种罕见的遗传性疾病，其特征是显著的早衰。典型的HGPS是由LMNA基因第11外显子（第1824位残基，C→T）的新生点突变引起的，激活了一个隐蔽的剪接供体，导致产生一种突变的核纤层蛋白A（LA），称为“早老素/LADelta50”，它缺乏去除C末端法尼基基团的正常切割位点。在间期，不可逆地法尼基化的早老素/LADelta50锚定在核膜上，并导致特征性的核泡形成。然而，早老素/LADelta50在有丝分裂期间的定位和行为完全未知。在这里，我们报告早老素/LADelta50在有丝分裂期间错误定位于不溶性细胞质聚集体和膜中，并导致异常的染色体分离和双核化。这些表型在很大程度上可以通过法尼基转移酶抑制剂或无法尼基化能力的突变型早老素/LADelta50得到挽救。此外，我们证明正常成纤维细胞中存在少量早老素/LADelta50，并且这些表达早老素/LADelta50的正常细胞中有相当比例是双核的，这表明早老素/LADelta50在正常衰老过程中也会导致类似的有丝分裂缺陷。我们的研究结果提供了HGPS中有丝分裂异常的证据，并可能为衰老的普遍现象提供线索。
