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Human Molecular Genetics Advance Access published online on May 11, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh154
© 2004 by Oxford University Press
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Article

Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome

Kenji Amano 1, Haruhiko Sago 2, Chiharu Uchikawa 1, Taishi Suzuki 3, Svetlana E. Kotliarova 3, Nobuyuki Nukina 3, Charles J. Epstein 4, Kazuhiro Yamakawa 1*

1 Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
2 Division of Fetal Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
3 Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
4 Department of Pediatrics, University of California, San Francisco, California 94143, USA

* To whom correspondence should be addressed. E-mail: yamakawa{at}brain.riken.jp.


  Abstract

Down syndrome (DS) is the most common chromosomally-caused form of mental retardation and is caused by trisomy for chromosome 21. The over-expression of genes located on the trisomic region has been assumed to be responsible for the phenotypic abnormalities of DS, but this hypothesis has not been fully confirmed and the very existence of gene dosage effects has been called into question. We have therefore investigated global gene expression profiles in Ts1Cje, a mouse model for DS that displays learning deficits and has a segmental trisomy of chromosome 16 orthologous to a segment of human chromosome 21 spanning from Sod1 to Znf295. DNA microarray analyses of six Ts1Cje and six normal littermate (2N) mouse brains at postnatal day 0 with probe sets representing ~11,300 genes revealed that the number of expressed genes and their identities in Ts1Cje mice were almost same in 2N mice. Notably, the expression levels of most genes in the trisomic region were increased about 1.5-fold, and the top 24 most consistently over-expressed genes in the Ts1Cje mice were all located on the trisomic region. In contrast, the expression levels of genes on other chromosomes or the euploid region of chromosome 16 were largely the same (1.0-fold) in Ts1Cje and 2N mice. These results indicate that the genes in the trisomic region of Ts1Cje are over-expressed in a dosage-dependent manner and are implicated in the molecular pathogenesis of DS.


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