NORMAL AND EXPANDED HUNTINGTONS-DISEASE GENE ALLELES PRODUCE DISTINGUISHABLE PROTEINS DUE TO TRANSLATION ACROSS THE CAG REPEAT

作者：PERSICHETTI F; AMBROSE CM; GE P; MCNEIL SM; SRINIDHI J; ANDERSON MA; JENKINS B; BARNES GT; DUYAO MP; KANALEY L; WEXLER NS; MYERS RH; BIRD ED; VONSATTEL JP; MACDONALD ME; GUSELLA JF

来源：Molecular Medicine, 1995, 1(4): 374-383.

Background: An expanded CAG trinudeotide 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.
Materials and Methods: 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.
Results: CAG repeat segments of both normal and expanded IID alleles are indeed translated, as part of a discrete similar to 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.
Conclusions: 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.

• 出版日期1995-5