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Title: Transgene copy number-dependent rescue of murine β-globin knockout mice carrying a 183 kb human β-globin BAC genomic fragment
Authors: Jim Vadolas
Hady Wardan
Marco Bosmans
Faten Zaibak
Duangporn Jamsai
Lucille Voullaire
Robert Williamson
Panos A. Ioannou
University of Melbourne
The Institute of Science and Technology for Research and Development, Mahidol University
Cyprus Institute of Neurology and Genetics
Royal Children's Hospital, Melbourne
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-May-2005
Citation: Biochimica et Biophysica Acta - Gene Structure and Expression. Vol.1728, No.3 (2005), 150-162
Abstract: We report the generation and characterisation of the first transgenic mice exclusively expressing normal human β-globin (huβ-globin) from a 183 kb genomic fragment. Four independent lines were generated, each containing 2-6 copies of thehuβ-globin locus at a single integration site. Steady state levels ofhuβ-globin protein were dependent on transgene copy number, but independent of the site of integration. Hemizygosity for the transgene on a heterozygous knockout background (huβ+/0,muβth-3/+) complemented fully the hematological abnormalities associated with the heterozygous knockout mutation in all four lines. Importantly, the rescue of the embryonic lethal phenotype that is characteristic of homozygosity for the knockout mutation was also demonstrated in two transgenic lines that were homozygous for two copies of thehuβ-globin locus, and in one transgenic line, which was hemizygous for six copies of thehuβ- globin locus. Our results illustrate the importance of transgene copy number determination and of the hemizygosity/homozygosity status in phenotypic complementation studies of transgenic mice containing large heterologous transgenes. Transgenic mouse colonies with 100%huβ-globin production from the intacthuβ-globin locus have been established and will be invaluable in comparative and gene therapy studies with mouse models containing specific β-thalassemia mutations in thehuβ-globin locus. © 2005 Elsevier B.V. All rights reserved.
ISSN: 01674781
Appears in Collections:Scopus 2001-2005

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