Aziz N Ahmad, van Belzen Martine J, Coops Ilona D, Belfroid René D M, Roos Raymund A C
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
Eur J Med Genet. 2011 Jul-Aug;54(4):e413-8. doi: 10.1016/j.ejmg.2011.04.002. Epub 2011 Apr 23.
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.
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.
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 (β=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 (β=-0.07; p=0.029). Parental age, offspring gender and season of conception were not related to CAG repeat instability.
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.
亨廷顿舞蹈症（HD）是一种由亨廷顿基因（HTT）中CAG重复序列扩增引起的常染色体显性进行性神经退行性疾病。然而，突变型HTT的CAG结构域在代际传递时不稳定，其潜在机制却鲜为人知。
从莱顿大学医学中心的HD档案中，挑选出所有涉及36个及以上CAG重复序列的亲代-子代对的DNA样本。为尽量减少操作变异性，采用相同的标准化方案重新评估突变型和正常型HTT中的CAG重复长度，从而确定了337次亲代-子代传递。评估了亲代特征（突变型和正常型CAG重复序列大小、年龄和性别）以及子代特征（性别和受孕季节）对CAG重复序列不稳定性的影响。
父系传递常与CAG重复序列扩增相关，而母系传递主要导致CAG重复序列收缩（平均变化：+1.76对-0.07，p<0.001）。仅在父系传递中，较大的突变型CAG重复序列大小与更高程度的CAG重复序列扩增相关（β=0.73；p<0.001）。相反，仅在母系传递中，正常等位基因较大的CAG重复序列大小与更高程度的CAG重复序列收缩相关（β=-0.07；p=0.029）。亲代年龄、子代性别和受孕季节与CAG重复序列不稳定性无关。
我们的研究结果表明，在代际传递过程中，突变型HTT的CAG重复序列存在轻微的母系收缩偏差，而非父系扩增偏差，且仅在母系中，这种偏差与正常HTT的CAG重复序列大小相关。
