International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Oral Presentation

Wednesday 20 November

17:15 - 17:30 HRS


L.E. Olson
Johns Hopkins University School of Medicine

Co-Authors: Reeves RH
Institutions: Johns Hopkins University School of Medicine

Down syndrome (DS), the most common viable autosomal aneuploidy, is caused by trisomy 21.  However, the mechanism by which increased gene dosage causes any specific DS feature is not yet established.  A “Down syndrome critical region” (DSCR) of Chr 21 has been proposed based on determining the smallest region in common among partially trisomic individuals who display the same DS feature.  Most reports include a region of about 5 Mb (~15% of Chr 21) in band q22.2-3 containing approximately 30 genes.  To date there has been neither a DS individual nor a mouse model trisomic for the DSCR alone. Using Cre-LoxP chromosomal engineering, we have created a deletion and a duplication of the DSCR in ES cells. We targeted LoxP sites to the proximal and distal borders of the DSCR conserved on mouse Chr 16.  These loxP sites are separated by 3.9 Mb in trans after two homologous recombination events. Transient transfection of Cre recombinase induced recombination between the two LoxP sites, resulting in a reciprocal deletion and duplication of the DSCR. These ES cells were karyotypically normal after three successive transfections and antiobiotic selections, and produced robust chimeric mice as evident by coat color.  Chimeras with these translocation products are being bred to wild type mice in order to create mice that are monosomic and trisomic for the DSCR.  We will directly test the DSCR hypothesis by evaluating phenotypes with exact parallels to those in DS.

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