MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington's disease mice.
MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington's disease mice.
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DOI：
10.1371/journal.pgen.1003280
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Pearson CE
中科院分区：
文献类型：
--
作者：
Tomé S;Manley K;Simard JP;Clark GW;Slean MM;Swami M;Shelbourne PF;Tillier ER;Monckton DG;Messer A;Pearson CE
体细胞组织中三核苷酸CAG/CTG重复序列的扩增被认为有助于在患有亨廷顿病或强直性肌营养不良的受影响个体的一生中持续的疾病进展。广泛的重复不稳定性之间出现的个人扩展重复，这表明存在的重复不稳定性的修饰符。具有扩增的CAG/CTG重复序列的小鼠根据小鼠品系显示可变水平的不稳定性。然而，到目前为止，这些差异背后的遗传修饰剂尚未确定。我们发现，在肝脏和纹状体的R6/1亨廷顿氏病（HD）（CAG）的R100转基因，当存在于同源C57 BL/6 J（B6）的背景下，发生扩展偏向的重复突变，而重复是稳定的同源BALB/cByJ（CBy）的背景。相互同源小鼠揭示了Msh 3基因作为重复不稳定性差异的决定因素。在CBy背景下B6 Msh 3基因纯合的同类小鼠中观察到扩增偏倚，而在B6背景下CBy Msh 3基因纯合的同类小鼠中CAG道稳定。CAG的稳定性与Msh 2的遗传缺陷一样显著。B6和CBy Msh 3基因具有相同的启动子，但编码区不同，并且显示出显著不同的蛋白质水平。B6 MSH 3变体蛋白高度表达并与CAG扩增相关，而CBy MSH 3变体蛋白以几乎不可检测的水平表达，与CAG稳定性相关。DHFR蛋白质，这是从Msh 3基因共享的启动子分化转录，没有显示不同的小鼠品系之间的水平。因此，天然存在的MSH 3蛋白多态性是CAG重复不稳定性的修饰剂，可能通过可变的MSH 3蛋白稳定性。由于有证据支持体细胞CAG不稳定性是疾病的一种修饰因子和预测因子，我们的数据与以下假设一致：与DNA修复基因多态性相关的CAG不稳定性的可变水平可能对各种重复相关疾病具有预后意义。特定基因中重复DNA序列的遗传不稳定性可导致许多神经退行性疾病、神经系统疾病和神经肌肉疾病。这些疾病在受影响个体的一生中表现出逐渐增加的症状严重程度，这种现象与随着人的年龄增长而增加的重复序列的不稳定性有关。个体之间的这种不稳定性水平存在差异，这种差异的来源是未知的。我们已经在重复不稳定的小鼠模型中表明，特定DNA修复基因MSH 3的微小差异（其蛋白质已知可以修复断裂的DNA）可能导致不同水平的重复不稳定性。这些DNA修复变体导致不同的修复蛋白水平，其中较低的水平导致降低的重复不稳定性。我们的研究结果表明，在受影响的人中，DNA修复基因的这种自然发生的变异可能是疾病进展的预测因子。此外，我们的研究结果支持这样的概念，即药物减少MSH 3蛋白应该减少重复不稳定性和疾病进展。
Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)∼100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases. The genetic instability of repetitive DNA sequences in particular genes can lead to numerous neurodegenerative, neurological, and neuromuscular diseases. These diseases show progressively increasing severity of symptoms through the life of the affected individual, a phenomenon that is linked with increasing instability of the repeated sequences as the person ages. There is variability in the levels of this instability between individuals—the source of this variability is unknown. We have shown in a mouse model of repeat instability that small differences in a certain DNA repair gene, MSH3, whose protein is known to fix broken DNA, can lead to variable levels of repeat instability. These DNA repair variants lead to different repair protein levels, where lower levels lead to reduced repeat instability. Our findings reveal that such naturally occurring variations in DNA repair genes in affected humans may serve as a predictor of disease progression. Moreover, our findings support the concept that pharmacological reduction of MSH3 protein should reduce repeat instability and disease progression.
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影响因子：
6.1
作者：
Dragileva, Ella;Hendricks, Audrey;Teed, Allison;Gillis, Tammy;Lopez, Edith T.;Friedberg, Errol C.;Kucherlapati, Raju;Edelmann, Winfried;Lunetta, Kathryn L.;MacDonald, Marry E.;Wheeler, Vanessa C.
通讯作者：
Wheeler, Vanessa C.
影响因子：
16.8
作者：
Cleary, John D.;Tome, Stephanie;Pearson, Christopher E.
通讯作者：
Pearson, Christopher E.
影响因子：
2.5
作者：
Cowin, Randi-Michelle;Nghiem Bui;Graham, Deanna;Green, Jennie R.;Yuva-Paylor, Lisa A.;Weiss, Andreas;Paylor, Richard
通讯作者：
Paylor, Richard
影响因子：
5.3
作者：
DEROOIJ, KE;GANS, PAMD;DENDUNNEN, JT
通讯作者：
DENDUNNEN, JT
影响因子：
3.7
作者：
Cowin, Randi-Michelle;Bui, Nghiem;Paylor, Richard
通讯作者：
Paylor, Richard