Persichetti F, Ambrose C M, Ge P, McNeil S M, Srinidhi J, Anderson M A, Jenkins B, Barnes G T, Duyao M P, Kanaley L
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129-2060, USA.
Mol Med. 1995 May;1(4):374-83.
An expanded CAG trinucleotide repeat is the genetic trigger of neuronal degeneration in Huntington's disease (HD), but its mode of action has yet to be discovered. The sequence of the HD gene places the CAG repeat near the 5' end in a region where it may be translated as a variable polyglutamine segment in the protein product, huntingtin.
Antisera directed at amino acid stretches predicted by the DNA sequence upstream and downstream of the CAG repeat were used in Western blot and immunohistochemical analyses to examine huntingtin expression from the normal and the HD allele in lymphoblastoid cells and postmortem brain tissue.
CAG repeat segments of both normal and expanded HD alleles are indeed translated, as part of a discrete approximately 350-kD protein that is found primarily in the cytosol. The difference in the length of the N-terminal polyglutamine segment is sufficient to distinguish normal and HD huntingtin in a Western blot assay.
The HD mutation does not eliminate expression of the HD gene but instead produces an altered protein with an expanded polyglutamine stretch near the N terminus. Thus, HD pathogenesis is probably triggered by an effect at the level of huntingtin protein.
CAG三核苷酸重复序列的扩增是亨廷顿舞蹈病（HD）神经元变性的遗传触发因素，但其作用方式尚未明确。HD基因序列使CAG重复序列位于5'端附近的一个区域，在该区域它可能作为蛋白质产物亨廷顿蛋白中可变的聚谷氨酰胺片段进行翻译。
针对CAG重复序列上下游DNA序列预测的氨基酸片段的抗血清用于蛋白质印迹和免疫组织化学分析，以检测淋巴母细胞和死后脑组织中正常及HD等位基因的亨廷顿蛋白表达。
正常和扩增的HD等位基因的CAG重复序列片段确实被翻译，作为一种主要存在于细胞质中的约350-kD离散蛋白的一部分。N端聚谷氨酰胺片段长度的差异足以在蛋白质印迹分析中区分正常和HD亨廷顿蛋白。
HD突变不会消除HD基因的表达，而是产生一种在N端附近有扩增聚谷氨酰胺延伸的改变蛋白。因此，HD发病机制可能是由亨廷顿蛋白水平的效应触发的。
