caa a22 4500 397575912 CHVBK 20180308164856.0 cr unu---uuuuu 161202e199612 xx s 000 0 eng 10.1093/hmg/5.12.1875 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.12.1875 Human Huntingtin Derived from YAC Transgenes Compensates for Loss of Murine Huntingtin by Rescue of the Embryonic Lethal Phenotype [Elektronische Daten] [J. Graeme Hodgson, Desmond J. Smith, Krista McCutcheon, H. Brook Koide, Kazutoshi Nishiyama, Mary Beth Dinulos, Mary E. Stevens, Nagat Bissada, Jamal Nasir, Ichiro Kanazawa, Christine M. Disteche, Edward M. Rubin, Michael R. Hayden] Huntington disease (HD) is caused by expansion of a CAG trinucleotide repeat in exon 1 of a novel gene. The HD protein (huntingtin) plays a critical role in early embryonic development since homozygous targeted disruption of the murine HD gene results in embryonic lethality by day 7.5. To rescue this phenotype by transgene based huntingtin expression it is therefore essential to express the protein early enough in development in the appropriate cells. Since YAC based transgenes are known to be regulated in an appropriate temporal and tissue-specific manner, we sought to rescue the embryonic lethality by breeding YAC transgenic mice expressing human huntingtin with mice heterozygous for the targeted disruption. We generated viable offspring homozygous for the disrupted murine HD gene but expressing human huntingtin derived from the YAC. This result clearly shows that YAC transgene based expression of huntingtin occurs prior to 7.5 days gestation. Additionally, we show that human huntingtin expression in YAC transgenic mice follows an identical tissue distribution and subcellular localisation pattern as that of the murine endogenous protein and that expression levels of 2-3 times endogenous can be achieved. This shows that human huntingtin under the influence of its native promoter, despite differences to the murine protein, is functional in a murine background and can compensate for loss of the murine protein. These results show that YAC transgenic approaches are a particularly promising route to producing an animal model for disorders associated with CAG expansion. © 1993 Oxford University Press Hodgson J. Graeme Department of Pathology, University of Washington, Seattle, WA 98105, USA aut Smith Desmond J. Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Building, Vancouver, BC V6T 1Z4, Canada aut McCutcheon Krista Department of Pathology, University of Washington, Seattle, WA 98105, USA aut Koide H. Brook Department of Pathology, University of Washington, Seattle, WA 98105, USA aut Nishiyama Kazutoshi Human Genome Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA aut Dinulos Mary Beth Department of Neurology, Institute for Brain Research, School of Medicine, University of Tokyo, Tokyo, Japan aut Stevens Mary E. Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Building, Vancouver, BC V6T 1Z4, Canada aut Bissada Nagat Department of Pathology, University of Washington, Seattle, WA 98105, USA aut Nasir Jamal Department of Pathology, University of Washington, Seattle, WA 98105, USA aut Kanazawa Ichiro Human Genome Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA aut Disteche Christine M. Department of Neurology, Institute for Brain Research, School of Medicine, University of Tokyo, Tokyo, Japan aut Rubin Edward M. Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Building, Vancouver, BC V6T 1Z4, Canada aut Hayden Michael R. Department of Pathology, University of Washington, Seattle, WA 98105, USA aut Human Molecular Genetics Oxford University Press 5/12(1996-12), 1875-1885 0964-6906 5:12<1875 1996 5 hmg https://doi.org/10.1093/hmg/5.12.1875 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.12.1875 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hodgson J. Graeme Department of Pathology, University of Washington, Seattle, WA 98105, USA aut NATIONALLICENCE 700 1- Smith Desmond J. Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Building, Vancouver, BC V6T 1Z4, Canada aut NATIONALLICENCE 700 1- McCutcheon Krista Department of Pathology, University of Washington, Seattle, WA 98105, USA aut NATIONALLICENCE 700 1- Koide H. Brook Department of Pathology, University of Washington, Seattle, WA 98105, USA aut NATIONALLICENCE 700 1- Nishiyama Kazutoshi Human Genome Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA aut NATIONALLICENCE 700 1- Dinulos Mary Beth Department of Neurology, Institute for Brain Research, School of Medicine, University of Tokyo, Tokyo, Japan aut NATIONALLICENCE 700 1- Stevens Mary E. Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Building, Vancouver, BC V6T 1Z4, Canada aut NATIONALLICENCE 700 1- Bissada Nagat Department of Pathology, University of Washington, Seattle, WA 98105, USA aut NATIONALLICENCE 700 1- Nasir Jamal Department of Pathology, University of Washington, Seattle, WA 98105, USA aut NATIONALLICENCE 700 1- Kanazawa Ichiro Human Genome Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA aut NATIONALLICENCE 700 1- Disteche Christine M. Department of Neurology, Institute for Brain Research, School of Medicine, University of Tokyo, Tokyo, Japan aut NATIONALLICENCE 700 1- Rubin Edward M. Department of Medical Genetics, University of British Columbia, 416-2125 East Mall, NCE Building, Vancouver, BC V6T 1Z4, Canada aut NATIONALLICENCE 700 1- Hayden Michael R. Department of Pathology, University of Washington, Seattle, WA 98105, USA aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/12(1996-12), 1875-1885 0964-6906 5:12<1875 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