背景:Friedreich共济失调是一种进行性多系统疾病,由共济失调蛋白缺乏引起;共济失调蛋白是一种参与铁硫簇合成的小线粒体蛋白。存在两种类型的共济失调蛋白:FXN-M,在大多数细胞中发现,FXN-E,几乎只在红细胞中发现。临床试验中的治疗包括通过基因疗法恢复共济失调蛋白,蛋白质替代,和表观遗传疗法,所有这些都需要灵敏的测定法来评估共济失调蛋白水平。
方法:在本研究中,我们使用了基于三重四极杆质谱的检测方法,在106例FRDA患者的大型异质队列中,检测了两种类型的共济失调蛋白在血液中水平的特征.
结果:Frataxin水平(FXN-E和FXNM)通过回归模型中的GAA重复长度预测(R2值分别为0.51和0.27),相反,共济失调蛋白水平可预测临床状态,如通过改良的Friedreich共济失调量表评分和残疾状态(R2值=0.13-0.16)确定的。随着时间的推移,个体受试者的共济失调蛋白水平没有显著变化,除了起始密码子突变,FXN-E和FXN-M水平大致相等。在较小的亚组中考虑血红蛋白水平改善了FXN-E和FXN-M水平两者的预测,从(0.3-0.38至0.20-0.51)的R2值。
结论:目前的数据表明,血液中FXN-M和FXN-E水平的测定为评估其在特定临床环境中的补充提供了适当的生物流体。
BACKGROUND: Friedreich ataxia is a progressive multisystem disorder caused by deficiency of the protein frataxin; a small mitochondrial protein involved in iron sulfur cluster synthesis. Two types of frataxin exist: FXN-M, found in most cells, and FXN-E, found almost exclusively in red blood cells. Treatments in clinical trials include frataxin restoration by gene therapy, protein replacement, and epigenetic therapies, all of which necessitate sensitive assays for assessing frataxin levels.
METHODS: In the present study, we have used a triple quadrupole mass spectrometry-based assay to examine the features of both types of frataxin levels in blood in a large heterogenous cohort of 106 patients with FRDA.
RESULTS: Frataxin levels (FXN-E and FXN M) were predicted by GAA repeat length in regression models (R2 values = 0.51 and 0.27, respectively), and conversely frataxin levels predicted clinical status as determined by modified Friedreich Ataxia Rating scale scores and by disability status (R2 values = 0.13-0.16). There was no significant change in frataxin levels in individual subjects over time, and apart from start codon mutations, FXN-E and FXN-M levels were roughly equal. Accounting for hemoglobin levels in a smaller sub-cohort improved prediction of both FXN-E and FXN-M levels from R2 values of (0.3-0.38 to 0.20-0.51).
CONCLUSIONS: The present data show that assay of FXN-M and FXN-E levels in blood provides an appropriate biofluid for assessing their repletion in particular clinical contexts.