Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life
Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life
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DOI：
10.1016/j.ygeno.2007.04.001
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发表时间：
2007-07-01
期刊：
影响因子：
4.4
通讯作者：
Bidichandani, Saniav I.
中科院分区：
文献类型：
--
作者：
De Biase, Irene;Rasmussen, Astrid;Bidichandani, Saniav I.
Friedreich 共济失调 (FRDA) 患者的 FXN 基因中的 GAA 三联体重复等位基因扩展为纯合子。涉及背根神经节（DRG）的原发性神经变性导致进行性共济失调。虽然众所周知 DRG 本质上对 frataxin 缺乏敏感，但最近的观察也表明它们表现出年龄依赖性的 GAA 三联体重复突变的进一步扩展。尚未在 FRDA 患者中系统地研究躯体不稳定是否是进行性的。对扩展等位基因纯合的 18 周胎儿组织中的 2300 个类似分子进行“小池”PCR 分析，结果显示与成人组织相比，不稳定程度非常低（4.2% 与 30.6%，p < 0.0001）。来自多个患者和携带者的血液样本中的突变负荷随着年龄的增长而显着增加，范围从妊娠 18 周时的 7.5% 到 49 岁时的 78.7%（R=0.91；p=0.0001）。因此，FRDA 的体细胞不稳定性主要发生在早期胚胎发育后，并在整个生命过程中不断进展，这进一步支持了出生后体细胞不稳定性在疾病发病机制中的作用。 (c) 2007 Elsevier Inc. 保留所有权利。
Friedreich ataxia (FRDA) patients are homozygous for expanded GAA triplet-repeat alleles in the FXN gene. Primary neurodegeneration involving the dorsal root ganglia (DRG) results in progressive ataxia. While it is known that DRG are inherently sensitive to frataxin deficiency, recent observations also indicate that they show age-dependent, further expansion of the GAA triplet-repeat mutation. Whether somatic instability is progressive has not been systematically investigated in FRDA patients. "Small-pool" PCR analysis of similar to 2300 individual molecules from tissues of an 18-week fetus homozygous for expanded alleles revealed very low levels of instability compared with adult-derived tissues (4.2% versus 30.6%, p < 0.0001). Mutation load in blood samples from multiple patients and carriers increased significantly with age, ranging from 7.5% at 18-weeks gestation to 78.7% at 49 years of age (R=0.91; p=0.0001). Therefore, somatic instability in FRDA occurs mostly after early embryonic development and progresses throughout life, lending further support to the role of postnatal somatic instability in disease pathogenesis. (c) 2007 Elsevier Inc. All rights reserved.