Ordway J M, Tallaksen-Greene S, Gutekunst C A, Bernstein E M, Cearley J A, Wiener H W, Dure L S, Lindsey R, Hersch S M, Jope R S, Albin R L, Detloff P J
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 35294, USA.
Cell. 1997 Dec 12;91(6):753-63. doi: 10.1016/s0092-8674(00)80464-x.
The mutations responsible for several human neurodegenerative disorders are expansions of translated CAG repeats beyond a normal size range. To address the role of repeat context, we have introduced a 146-unit CAG repeat into the mouse hypoxanthine phosphoribosyltransferase gene (Hprt). Mutant mice express a form of the HPRT protein that contains a long polyglutamine repeat. These mice develop a phenotype similar to the human translated CAG repeat disorders. Repeat containing mice show a late onset neurological phenotype that progresses to premature death. Neuronal intranuclear inclusions are present in affected mice. Our results show that CAG repeats do not need to be located within one of the classic repeat disorder genes to have a neurotoxic effect.
导致几种人类神经退行性疾病的突变是翻译后的CAG重复序列扩展至超出正常大小范围。为了研究重复序列背景的作用，我们将一个146个单位的CAG重复序列导入小鼠次黄嘌呤磷酸核糖转移酶基因（Hprt）。突变小鼠表达一种含有长聚谷氨酰胺重复序列的HPRT蛋白形式。这些小鼠表现出与人类翻译后的CAG重复序列疾病相似的表型。含有重复序列的小鼠表现出迟发性神经表型，并进展为过早死亡。受影响的小鼠存在神经元核内包涵体。我们的结果表明，CAG重复序列无需位于经典重复序列疾病基因之一内即可产生神经毒性作用。
