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ID: 535983.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function.
Authors:Trimborn, Marc; Ghani, Mahdi; Walther, Diego J.; Dopatka, Monika; Dutrannoy, Véronique; Busche, Andreas; Meyer, Franziska; Nowak, Stefanie; Nowak, Jean N; Zabel, Claus; Klose, Joachim; Esquitino, Veronica; Garshasbi, Masoud; Kuss, Andreas W.; Ropers, Hans-Hilger; Mueller, Susanne; Poehlmann, Charlotte; Gavvovidis, Ioannis; Schindler, Detlev; Sperling, Karl; Neitzel, Heidemarie
Language:English
Research Context:This research was supported by funding from the Deutsche Forschungsgemeinschaft (NE 531/5-3) to H.N. and K.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date of Publication (YYYY-MM-DD):2010-02-16
Title of Journal:PLoS ONE
Journal Abbrev.:PLoS ONE
Volume:5
Issue / Number:2
Start Page:e9242.
End Page:e9242.
Full name of Issue-Editor(s):Joanna Mary Bridger
Copyright:Trimborn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Mutations in the human gene MCPH1 cause primary microcephaly associated with a unique cellular phenotype with premature chromosome condensation (PCC) in early G2 phase and delayed decondensation post-mitosis (PCC syndrome). The gene encodes the BRCT-domain containing protein microcephalin/BRIT1. Apart from its role in the regulation of chromosome condensation, the protein is involved in the cellular response to DNA damage. We report here on the first mouse model of impaired Mcph1-function. The model was established based on an embryonic stem cell line from BayGenomics (RR0608) containing a gene trap in intron 12 of the Mcph1 gene deleting the C-terminal BRCT-domain of the protein. Although residual wild type allele can be detected by quantitative real-time PCR cell cultures generated from mouse tissues bearing the homozygous gene trap mutation display the cellular phenotype of misregulated chromosome condensation that is characteristic for the human disorder, confirming defective Mcph1 function due to the gene trap mutation. While surprisingly the DNA damage response (formation of repair foci, chromosomal breakage, and G2/M checkpoint function after irradiation) appears to be largely normal in cell cultures derived from Mcph1gt/gt mice, the overall survival rates of the Mcph1gt/gt animals are significantly reduced compared to wild type and heterozygous mice. However, we could not detect clear signs of premature malignant disease development due to the perturbed Mcph1 function. Moreover, the animals show no obvious physical phenotype and no reduced fertility. Body and brain size are within the range of wild type controls. Gene expression on RNA and protein level did not reveal any specific pattern of differentially regulated genes. To the best of our knowledge this represents the first mammalian transgenic model displaying a defect in mitotic chromosome condensation and is also the first mouse model for impaired Mcph1-function.
Comment of the Author/Creator:E-mail: heidemarie.neitzel@charite.de
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institute for Medical Genetics, Charité – Universitätsmedizin Berlin, Berlin, Germany;
2.Institute of Human Genetics, Charité – Universitätsmedizin Berlin, Berlin, Germany;
3.Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Berlin, Germany;
4.Institute of Human Genetics, University Wuerzburg, Wuerzburg, Germany;
Identifiers:URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC282193...
ISSN:1932-6203
DOI:10.1371/journal.pone.0009242.
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