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  Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function.

Trimborn, M., Ghani, M., Walther, D. J., Dopatka, M., Dutrannoy, V., Busche, A., et al. (2010). Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function. PLoS ONE, 5(2), e9242.-e9242. doi:10.1371/journal.pone.0009242.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7BD8-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7BD9-0
Genre: Journal Article
Alternative Title : PLoS ONE

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Trimborn, Marc, Author
Ghani, Mahdi, Author
Walther, Diego J.1, Author              
Dopatka, Monika2, Author
Dutrannoy, Véronique, Author
Busche, Andreas, Author
Meyer, Franziska, Author
Nowak, Stefanie, Author
Nowak, Jean N, Author
Zabel, Claus, Author
Klose, Joachim, Author
Esquitino, Veronica, Author
Garshasbi, Masoud1, Author              
Kuss, Andreas W.3, Author              
Ropers, Hans-Hilger1, Author              
Mueller, Susanne, Author
Poehlmann, Charlotte, Author
Gavvovidis, Ioannis, Author
Schindler, Detlev, Author
Sperling, Karl, Author
Neitzel, Heidemarie, Author more..
Affiliations:
1Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, escidoc:1433549              
2Max Planck Society, escidoc:persistent13              
3Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, escidoc:1479644              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2010-02-16
 Publication Status: Published in print
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Title: PLoS ONE
  Alternative Title : PLoS ONE
Source Genre: Journal
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Pages: - Volume / Issue: 5 (2) Sequence Number: - Start / End Page: e9242. - e9242. Identifier: ISSN: 1932-6203