caa a22 4500 397574355 CHVBK 20180308164851.0 cr unu---uuuuu 161202e199602 xx s 000 0 eng 10.1093/hmg/5.2.177 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.2.177 Absence of Disease Phenotype and Intergenerational Stability of the Cag Repeat in Transgenic Mice Expressing the Human Huntington Disease Transcript [Elektronische Daten] [Y. P. Goldberg, M. A. Kalchman, M. Metzler, J. Nasir, J. Zeisler, R. Graham, H. B. Koide, J. O'Kusky, A. H. Sharp, C. A. Ross, F. Jirik, M. R. Hayden] The mutation underlying Huntington disease (HD) is CAG expansion in the first exon of the HD gene. In order to investigate the role of CAG expansion in the pathogenesis of HD, we have produced transgenic mice containing the full length human HD cDNA with 44 CAG repeats. By 1 year, these mice have no behavioral abnormalities and morphometric analysis at 6 (one animal) and 9 (two animals) months age revealed no changes. Despite high levels of mRNA expression, there was no evidence of the HD gene product in any of these transgenic mice. In vitro transfection studies indicated that the inclusion of 120 bp of the 5′ UTR in the cDNA construct and the presence of a frameshift mutation at nucleotide 2349 prevented expression of the HD cDNA. These findings suggest that the pathogenesis of HD is not mediated through DNA-protein interaction and that presence of the RNA transcript with an expanded CAG repeat is insufficient to cause the disease. Rather, translation of the CAG is crucial for the pathogenesis of HD. In contrast to that seen in humans, the CAG repeat in these mice was remarkably stable in 97 meioses. This suggests that genomic sequences may play a critical role in influencing repeat instability. © 1996 Oxford University Press Goldberg Y. P. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut Kalchman M. A. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut Metzler M. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut Nasir J. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut Zeisler J. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut Graham R. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut Koide H. B. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut O'Kusky J. Laboratory of Molecular Neurobiology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA aut Sharp A. H. Department of Pathology and Laboratory Medicine, University of British Columbia,Vancouver, BC Canada aut Ross C. A. Department of Pathology and Laboratory Medicine, University of British Columbia,Vancouver, BC Canada aut Jirik F. Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada aut Hayden M. R. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut Human Molecular Genetics Oxford University Press 5/2(1996-02), 177-185 0964-6906 5:2<177 1996 5 hmg https://doi.org/10.1093/hmg/5.2.177 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.2.177 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Goldberg Y. P. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Kalchman M. A. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Metzler M. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Nasir J. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Zeisler J. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Graham R. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Koide H. B. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- O'Kusky J. Laboratory of Molecular Neurobiology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA aut NATIONALLICENCE 700 1- Sharp A. H. Department of Pathology and Laboratory Medicine, University of British Columbia,Vancouver, BC Canada aut NATIONALLICENCE 700 1- Ross C. A. Department of Pathology and Laboratory Medicine, University of British Columbia,Vancouver, BC Canada aut NATIONALLICENCE 700 1- Jirik F. Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 700 1- Hayden M. R. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/2(1996-02), 177-185 0964-6906 5:2<177 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford