Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington's disease
Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington's disease
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DOI：
10.1016/j.ejmg.2011.04.002
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发表时间：
2011-07-01
影响因子：
1.9
通讯作者：
Roos, Raymund A. C.
中科院分区：
文献类型：
--
作者：
Aziz, N. Ahmad;van Belzen, Martine J.;Roos, Raymund A. C.
背景资料：亨廷顿病（HD）是一种进行性常染色体显性遗传性神经退行性疾病，由HD基因（HTT）中的CAG重复扩增引起。突变HTT的CAG域是不稳定的代际传递后，然而，鲜为人知的基本mechanism.Methods：从HD档案的莱顿大学医学中心的DNA样本，从所有的父母，后代对涉及36 CAG重复或更多的选择。为了最大限度地减少程序的变化，CAG重复序列长度在突变和正常HTT使用相同的标准化协议，这导致在337亲子传播的识别进行了重新评估。结果：CAG重复序列的扩增与父源遗传有关，而母源遗传主要导致CAG重复序列的收缩（平均变化：+1.76vs.-0.07，p < 0.001）。只有在父系遗传中，更大的突变CAG重复序列大小与更大程度的CAG重复序列扩增相关（β = 0.73; p < 0.001）。相反，只有在母体传递中，正常等位基因的CAG重复序列大小越大，CAG重复序列收缩程度越大（β = -0.07; p = 0.029）。父母的年龄，后代的性别和季节的概念是不相关的CAG重复stability.Conclusion：我们的研究结果表明，轻微的母体收缩的偏见，而不是一个父亲的扩展偏见的突变HTT CAG重复在代际传递，这只在母系与正常HTT CAG重复大小。(C)2011年Elsevier Masson SAS。All rights reserved.
Background: Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). The CAG domain of mutant HTT is unstable upon intergenerational transmission, however, little is known about the underlying mechanisms.Methods: From the HD archives of the Leiden University Medical Centre DNA samples from all parent-offspring pairs involving 36 CAG repeats or more were selected. To minimize procedural variability, CAG repeat lengths in both mutant and normal HTT were reassessed using the same standardized protocol, which resulted in the identification of 337 parent-offspring transmissions. The effects of both parental (mutant and normal CAG repeat size, age and gender) and offspring (gender and season of conception) characteristics on CAG repeat instability were assessed.Results: Paternal transmissions were often associated with CAG repeat expansion, whereas maternal transmissions mainly resulted in CAG repeat contraction (mean change: +1.76 vs. -0.07, p < 0.001). Only in paternal transmissions larger mutant CAG repeat size was associated with a greater degree of CAG repeat expansion (beta = 0.73; p < 0.001). Conversely, only in maternal transmissions larger CAG repeat size of the normal allele was associated with a greater degree of CAG repeat contraction (beta = -0.07; p = 0.029). Parental age, offspring gender and season of conception were not related to CAG repeat instability.Conclusion: Our findings suggest a slight maternal contraction bias as opposed to a paternal expansion bias of the mutant HTT CAG repeat during intergenerational transmission, which only in the maternal line is associated with normal HTT CAG repeat size. (C) 2011 Elsevier Masson SAS. All rights reserved.