Quantification of Farnesylated Progerin in Hutchinson-Gilford Progeria Patient Cells by Mass Spectrometry.
Quantification of Farnesylated Progerin in Hutchinson-Gilford Progeria Patient Cells by Mass Spectrometry.
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DOI：
10.3390/ijms231911733
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发表时间：
2022-10-03
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Hutchinson-Gilford早衰综合征（HGPS）是一种罕见的致命疾病，其特征是过早衰老和死亡，中位年龄为14.5岁。HGPS最常见的原因（影响约90%的患者）是LMNA基因中的从头杂合同义单碱基取代（c.1824C>T; p.G608G），其导致早老蛋白的积累，早老蛋白是核纤层蛋白A的异常形式，与成熟核纤层蛋白A不同，其保持永久法尼基化。早老蛋白与成熟核纤层蛋白A的比率与HGPS患者的疾病严重程度相关，并且可用于评估旨在减少异常剪接或早老蛋白法尼基化的疗法的有效性。我们最近表明，核纤层蛋白A和早老蛋白的内源性含量可以通过质谱法（MS）测量，提供了一种替代免疫学方法，缺乏必要的特异性和定量准确性。在这里，我们提出了第一个非免疫学的方法，可靠地定量水平的野生型核纤层蛋白A和法尼基化的早老蛋白的细胞从HGPS患者。该方法基于靶向MS方法和使用同位素标记的内标物，可应用于正在进行的临床试验，以评估抑制早老蛋白法尼基化的药物的疗效。
Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal disorder characterized by premature aging and death at a median age of 14.5 years. The most common cause of HGPS (affecting circa 90% of patients) is a de novo heterozygous synonymous single-base substitution (c.1824C>T; p.G608G) in the LMNA gene that results in the accumulation of progerin, an aberrant form of lamin A that, unlike mature lamin A, remains permanently farnesylated. The ratio of progerin to mature lamin A correlates with disease severity in HGPS patients, and can be used to assess the effectiveness of therapies aimed at lessening aberrant splicing or progerin farnesylation. We recently showed that the endogenous content of lamin A and progerin can be measured by mass spectrometry (MS), providing an alternative to immunological methods, which lack the necessary specificity and quantitative accuracy. Here, we present the first non-immunological method that reliably quantifies the levels of wild-type lamin A and farnesylated progerin in cells from HGPS patients. This method, which is based on a targeted MS approach and the use of isotope-labeled internal standards, could be applied in ongoing clinical trials evaluating the efficacy of drugs that inhibit progerin farnesylation.
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