Frataxin levels in peripheral tissue in Friedreich ataxia.
Frataxin levels in peripheral tissue in Friedreich ataxia.
复制标题
DOI：
10.1002/acn3.225
复制
发表时间：
2015-08
影响因子：
5.3
通讯作者：
Lynch DR
中科院分区：
文献类型：
--
作者：
Lazaropoulos M;Dong Y;Clark E;Greeley NR;Seyer LA;Brigatti KW;Christie C;Perlman SL;Wilmot GR;Gomez CM;Mathews KD;Yoon G;Zesiewicz T;Hoyle C;Subramony SH;Brocht AF;Farmer JM;Wilson RB;Deutsch EC;Lynch DR
弗里德赖希共济失调（FRDA）是由共济失调蛋白基因（FXN）突变引起的常染色体隐性共济失调。此类突变通常是扩大的鸟嘌呤-腺嘌呤-腺嘌呤（GAA）重复序列，会导致受影响和未受影响组织中共济失调蛋白水平降低。目的是了解外周组织中共济失调蛋白水平与疾病状态的关系。测量口腔细胞和血液中的Frataxin水平，并分析其与疾病特征的关系。还将定点突变的共济失调蛋白转染到人胚肾细胞中，以模拟特定点突变的结果。重复测量分析没有证据表明共济失调蛋白水平随着时间的推移而变化，尽管横截面数据的线性回归分析预测了几十年来的小幅增加。GAA重复序列长度预测了两种组织中的共济失调蛋白水平，共济失调蛋白水平本身预测了神经系统评分（考虑年龄）。复合杂合子患者的GAA扩增和FXN的点突变通常有较低的水平共济失调蛋白比纯合子的存在两个GAA重复扩增，虽然水平显着变化的组织之间的一些复合杂合子点突变。G130 V突变导致体外和体内Frataxin水平降低，而R165 C突变在体外和体内均产生正常的Frataxin免疫反应水平。起始密码子突变导致口腔细胞中frataxin水平较低，但保留了血液中的免疫反应性frataxin水平。目前的数据表明，外周共济失调蛋白水平反映了FRDA的疾病特征，但强调需要在特定突变的背景下解释这种水平。
Friedreich ataxia (FRDA) is an autosomal recessive ataxia resulting from mutations in the frataxin gene (FXN). Such mutations, usually expanded guanine–adenine–adenine (GAA) repeats, give rise to decreased levels of frataxin protein in both affected and unaffected tissues. The goal was to understand the relationship of frataxin levels in peripheral tissues to disease status. Frataxin levels were measured in buccal cells and blood, and analyzed in relation to disease features. Site-directed mutant frataxin was also transfected into human embryonic kidney cells to model results from specific point mutations. There was no evidence for change in frataxin levels over time with repeated measures analysis, although linear regression analysis of cross-sectional data predicted a small increase over decades. GAA repeat length predicted frataxin levels in both tissues, and frataxin levels themselves predicted neurological ratings (accounting for age). Compound heterozygous patients for a GAA expansion and a point mutation in FXN generally had lower levels of frataxin than those homozygous for the presence of two GAA repeat expansions, though levels varied dramatically between tissues in some compound heterozygotes for point mutations. The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo. Start codon mutations led to low levels of frataxin in buccal cells but preserved immunoreactive frataxin levels in blood. The present data show that peripheral frataxin levels reflect disease features in FRDA, but emphasize the need for interpretation of such levels in the context of specific mutations.