International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Reeves R H
Johns Hopkins Schl. Med

Co-Authors: 1) Olson L E, 2) Baxter L L, 3) Carlson E J, 3) Epstein CJ
Institutions: 1) Johns Hopkins Schl. Med., 2) National Institutes of Health, 3) Univ. California Sna Francisco

The mechanisms by which trisomy 21 causes specific traits of Down syndrome (DS) are unknown. One “qualitative” hypothesis proposes that one or a few genes cause specific phenotypes of DS, while the “quantitative” hypothesis asserts that defects occur due to small effects of many genes. We evaluated cerebellar phenotypes of DS using mouse models. The Ts65Dn mouse is trisomic for approximately 113 genes found on HSA21; complementary subsets of 89 and 23 of these genes are trisomic in Ts1Cje and Ms1Cje/Ts65Dn mice, respectively. We calculated total cerebellar volume and cell densities of granule cells and Purkinje cells in Ts1Cje and Ms1Cje/Ts65Dn mice and previously in Ts65Dn (Baxter et al., Hum Mol Genet, 2000). Cerebellar volume was reduced to the same extent in Ts65Dn and Ts1Cje mice but not reduced in Ms1Cje/Ts65Dn. Granule cell density was equally affected in Ts1Cje and Ms1Cje/Ts65Dn, but to a lesser degree than in Ts65Dn. Purkinje cell density is significantly reduced in Ts65Dn mice but unaffected in either Ts1Cje or Ms1Cje/Ts65Dn mice. Neither the qualitative nor the quantitative hypothesis predicts these outcomes. A more useful description is whether a region of trisomy is necessary and/or sufficient to cause a phenotype. The region of trisomy sufficient to cause cerebellar reduction has been narrowed to the Ts1Cje region. The Ts1Cje and the Ms1Cje/Ts65Dn segments may have an added affect to produce the degree of granule cell deficiency seen in Ts65Dn, and neither of these regions is sufficient to cause Purkinje cell density reduction.

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