Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability.
Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability.
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携带 CAG 45 等位基因的雄激素受体 YAC 转基因小鼠表现出三核苷酸重复不稳定。
DOI：
10.1093/hmg/7.6.959
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发表时间：
1998
影响因子：
3.5
通讯作者：
G. McKnight
中科院分区：
文献类型：
--
作者：
A. Spada;K. Peterson;S. A. Meadows;M. E. McClain;G. Jeng;R. S. Chmelar;H. A. Haugen;K. Chen;M. J. Singer;David R. Moore;B. Trask;K. Fischbeck;Chris Clegg;G. McKnight
x连锁脊髓和球性肌萎缩症（SBMA）是由雄激素受体（AR）基因第一外显子CAG重复扩增引起的。疾病相关等位基因（37-66 cag）从父母遗传给后代时，长度会发生变化，当父亲遗传时，大小变化的趋势明显更大。由于携带具有45和66 CAG重复序列的人AR cdna的转基因小鼠不表现出重复不稳定性，我们试图通过产生酵母人工染色体（YACs）在其基因组背景下携带AR CAG重复扩增的转基因小鼠来模拟三核苷酸重复不稳定性。对具有CAG 45等位基因的AR - YAC转基因小鼠的独立品系的研究显示，代间不稳定性的总体比率约为10%。我们还发现，45 CAG重复束随着母体传播和传播母亲年龄的增长而明显更加不稳定。在迄今为止生产的所有CAG/CTG重复转基因小鼠中，AR YAC CAG 45小鼠是不稳定的，具有最小的三核苷酸重复突变，这表明通过包括适当的人类DNA序列可以降低小鼠重复不稳定的长度阈值。通过序列标记位点内容分析和长距离定位，我们确定由于AR YAC的断裂，一个不稳定的转基因品系整合了大约70 kb的AR位点片段。鉴定允许CAG通道不稳定的顺式作用元件和调节AR YAC CAG 45小鼠重复不稳定的反式作用因子可能为人类三核苷酸重复不稳定的分子基础提供见解。
X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis -acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.
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作者：
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DOI：
--
发表时间：
1993
期刊：
Transactions of the Association of American Physicians
影响因子：
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作者：
Peterson,KR;Clegg,CH;Huxley,C;Josephson,BM;Haugen,HS;Furukawa,T;Stamatoyannopoulos,G
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Stamatoyannopoulos,G